Fortschritte der Chemie

organischer Naturstoffe

Progress in the Chemistry

of Organic Natural Products

Founded by L. Zechmeister

Editors:
A. D. Kinghorn, Columbus, OH
H. Falk, Linz
J. Kobayashi, Sapporo

Honorary Editor:
W. Herz, Tallahassee, FL

Editorial Board:
V. M. Dirsch, Vienna
S. Gibbons, London
N. H. Oberlies, Greensboro, NC
Y. Ye, Shanghai
 92

Fortschritte der Chemie

organischer Naturstoffe

Progress in the Chemistry

of Organic Natural Products

Authors:
H. Budzikiewicz
R. Pereda-Miranda, D. Rosas-Ramı́rez,
and J. Castañeda-Gómez

SpringerWienNewYork
 Prof. A. Douglas Kinghorn, College of Pharmacy,
Ohio State University, Columbus, OH, USA

em. Univ.-Prof. Dr. H. Falk, Institut für Organische Chemie,

Johannes-Kepler-Universität, Linz, Austria

Prof. Dr. J. Kobayashi, Graduate School of Pharmaceutical Sciences,

Hokkaido University, Sapporo, Japan

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ISBN 978-3-211-99660-7 e-ISBN 978-3-211-99661-4
DOI 10.1007/ 978-3-211-99661-4
SpringerWienNewYork
Brief CV – Herbert Budzikiewicz

Herbert Budzikiewicz was born on February 20, 1933 in Vienna (Austria). He

received his Ph. D. in chemistry in 1959 from the University of Vienna. From 1961
to 1965, he was head of the mass spectrometry facilities of the Department of
Chemistry at Stanford University (CA, USA). From 1965 to 1969, he was at the
University of Braunschweig (Germany), where he received the venia legendi for
organic chemistry. In 1970, he became professor ordinarius at the Institute of
Organic Chemistry of the University at Köln (Germany). He was dean of the
Faculty of Sciences several times and since 1998, he has been emeritus.
The fields of research of Herbert Budzikiewicz are mass spectrometry and
natural products chemistry, in which he specialized in bacterial metabolites. He is
the author of over 500 research publications and he authored and co-authored
several books on mass spectrometry. In 2008, he received the Honor Medal of the
German Mass Spectrometry Society.

v
Brief CV – Rogelio Pereda-Miranda

Rogelio Pereda-Miranda is a native of Mexico City and completed his undergraduate

education in Biology at the Metropolitan Autonomous University in 1981.
He received his Ph.D. in Chemistry from the National Autonomous University of
Mexico (UNAM) in 1994. Following a postdoctoral fellowship at the Institutes
of Biology and Chemistry, University of Ottawa, he joined the faculty of the
Department of Pharmacy, School of Chemistry, UNAM, where he has been Full
Professor of Pharmacognosy. Dr. Pereda-Miranda has published 85 papers in plant
secondary metabolites with relevant medicinal and agrochemical importance. He
has had a long-standing interest in developing analytical methods for the isolation
of biodynamic principles by modern preparative chromatography techniques.
His research interests also include determination of the tridimensional structure
and molecular conformation by nuclear magnetic resonance spectroscopy and
molecular modeling of carbohydrates, oligosaccharides and complex secondary
metabolites. Currently, he is working in the chemical design and total synthesis
of new substances with antimicrobial, cytotoxic and antineoplasic activities based
on natural products.

vi
Brief CV – Daniel Rosas-Ramı́rez

Daniel Rosas-Ramı́rez was born in Mexico City. He obtained his B.Sc. (2006) from
La Salle University and his M.Sc. (2007) from the National Autonomous University
of Mexico (UNAM). As a Ph.D. student, he has spent two years at the Department
of Pharmacy, School of Chemistry, UNAM, working on the conformation by NMR
spectroscopy and crystal structure of sweet potato oligosaccharides.

vii
Brief CV – Jhon Castañeda-Gómez

Jhon Castañeda-Gómez is a native of Manizales, Colombia. He obtained his B.Sc

(1999) from the University of Caldas and his M.Sc. (2007) from Del Valle
University in Colombia. He has completed two years of the Ph.D. program at the
School of Chemistry, National Autonomous University of Mexico, and working at
the Department of Pharmacy on the development of analytical techniques for the
isolation of complex polysaccharides from plant sources.

viii
Contents

List of Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi

Microbial Siderophores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Herbert Budzikiewicz
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2. Peptide Siderophores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2.1. Pyoverdins and Related Siderophores from
Pseudomonas spp. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2.2. Azomonas and Azotobacter Siderophores . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
2.3. Anachelin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
2.4. Actinomycetal Metabolites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
2.5. Bacterial Hydroxamate Siderophores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
2.6. Fungal L-Ornithine-Based Hydroxamate Siderophores . . . . . . . . . . . . 12
2.7. Catecholate Siderophores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
2.8. Lipopeptidic Siderophores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
2.9. Pseudomonas mendocina Siderophores . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
3. Siderophores Based on Diamino- and Triaminoalkane
Skeletons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
3.1. Rhizobactin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
3.2. Catecholate Siderophores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
3.3. Hydroxamic Acid Siderophores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
4. Citrate Siderophores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
4.1. Siderophores with Two Hydroxamic Acid Units . . . . . . . . . . . . . . . . . . 29
4.2. Siderophores with 2-Oxoglutaric Acid Units . . . . . . . . . . . . . . . . . . . . . . 32
4.3. Siderophores with Two Catecholate Units . . . . . . . . . . . . . . . . . . . . . . . . 33
4.4. Siderophores with Two Citric Acid Units . . . . . . . . . . . . . . . . . . . . . . . . . 34
4.5. Legiobactin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
5. Pyochelin and Related Structures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
6. Miscellaneous Siderophores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
7. Fe2+ Binding Ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

ix
x Contents

8. Selected Syntheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
8.1. Anachelin H . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
8.2. Alterobactin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
8.3. Parabactin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
8.4. Nannochelin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
8.5. Pyochelin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
9. Epilog . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
Notes Added in Proof . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

Resin Glycosides from the Morning Glory Family . . . . . . . . . . . . . . . . . . . . . 77

Rogelio Pereda-Miranda, Daniel Rosas-Ramı´rez,
and Jhon Castañeda-Gómez
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
2. Ethnobotanical Background and Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
3. Structural Diversity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
3.1. Chemical Composition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
3.2. Resin Glycosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
4. Isolation Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
5. Structure Elucidation of Resin Glycosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
5.1. Degradative Chemical Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
5.2. Spectroscopic Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
5.3. Crystallographic Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
5.4. Molecular Modeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
6. Strategies for Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
6.1. Tricolorin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
6.2. Ipomoeassin E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
6.3. Woodrosin I . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
7. Significance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
7.1. Traditional Medicine and Morning Glories . . . . . . . . . . . . . . . . . . . . . . 140
7.2. Biological Activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
7.3. Pharmacology and Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
7.4. Chemical Ecology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147

Author Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155

Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169

Listed in PubMed
List of Contributors

Budzikiewicz, Prof. Dr. H., Institut für Organische Chemie, Universität zu Köln,
Greinstr. 4, 50939 Köln, Germany
e-mail: [email protected]

Castañeda-Gómez, Dr. J., Departamento de Farmacia, Facultad de Quı́mica,

Universidad Nacional Autónoma de México, Ciudad Universitaria, 04510 DF,
México
e-mail: [email protected]

Pereda-Miranda, Prof. Dr. R., Departamento de Farmacia, Facultad de Quı́mica,

Universidad Nacional Autónoma de México, Ciudad Universitaria, 04510 DF,
México
e-mail: [email protected]

Rosas-Ramı́rez, Dr. D., Departamento de Farmacia, Facultad de Quı́mica, Univer-

sidad Nacional Autónoma de México, Ciudad Universitaria, 04510 DF, México
e-mail: [email protected]

xi
Microbial Siderophores

Herbert Budzikiewicz

Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2. Peptide Siderophores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2.1. Pyoverdins and Related Siderophores from Pseudomonas spp. . . . . . . . . . . . . . . . . . . . . . 4
2.2. Azomonas and Azotobacter Siderophores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
2.3. Anachelin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
2.4. Actinomycetal Metabolites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
2.5. Bacterial Hydroxamate Siderophores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
2.6. Fungal L-Ornithine-Based Hydroxamate Siderophores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
2.7. Catecholate Siderophores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
2.8. Lipopeptidic Siderophores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
2.9. Pseudomonas mendocina Siderophores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
3. Siderophores Based on Diamino- and Triaminoalkane Skeletons . . . . . . . . . . . . . . . . . . . . . . . . 23
3.1. Rhizobactin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
3.2. Catecholate Siderophores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
3.3. Hydroxamic Acid Siderophores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
4. Citrate Siderophores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
4.1. Siderophores with Two Hydroxamic Acid Units . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
4.2. Siderophores with 2-Oxoglutaric Acid Units . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
4.3. Siderophores with Two Catecholate Units . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
4.4. Siderophores with Two Citric Acid Units . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
4.5. Legiobactin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
5. Pyochelin and Related Structures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
6. Miscellaneous Siderophores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
7. Fe2+ Binding Ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
8. Selected Syntheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
8.1. Anachelin H . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
8.2. Alterobactin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
8.3. Parabactin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

H. Budzikiewicz
Institut für Organische Chemie, Universität zu Köln, Greinstr. 4, 50939 Köln, Germany
e-mail: [email protected]

A.D. Kinghorn et al. (eds.), Fortschritte der Chemie organischer Naturstoffe / 1

Progress in the Chemistry of Organic Natural Products, Vol. 92,
DOI 10.1007/978-3-211-99661-4_1, # Springer-Verlag/Wien 2010
2 H. Budzikiewicz

8.4. Nannochelin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
8.5. Pyochelin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
9. Epilog . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
Notes Added in Proof . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

1. Introduction

Iron is of great importance for many metabolic processes since the redox potential
between its two valence states Fe2+ and Fe3+ lies within the range of physiological
processes. Actually, iron is not a rare element, it is fourth in abundance in the earth
crust, but it is not readily available for microorganisms. In the soil ferric oxide hydrates
are formed at pH values around seven and the concentration of free Fe3+ is at best
10
17 mol/dm3 while about 10
6 mol/dm3 would be needed. In living organisms iron
is usually strongly bound to peptidic substances such as transferrins. To increase the
supply of soluble iron microorganisms other than those living in an acidic habitat may
circumvent the problem by reduction of Fe3+ to Fe2+ (182), which seems to be of major
importance for marine phytoplankton (151); see also amphiphilic marine bacteria
(Sect. 2.8) and Fe2+ binding ligands (Sect. 7) below. An important alternative is the
production of Fe3+ chelating compounds, so-called siderophores. Siderophores are
secondary metabolites with masses below 2,000 Da and a high affinity to Fe3+. Small
iron-siderophore complexes can enter the cell via unspecific porins, larger ones need a
transport system that recognizes the ferri-siderophore at the cell surface. In the cell,
iron is released mostly by reduction to the less strongly bound Fe2+ state (137), and the
free siderophore is re-exported (“shuttle mechanism”); for a modified shuttle system
see pyoverdins (Sect. 2.1) and amonabactins (Sect. 2.7). Rarely the siderophore is
degraded in the periplasmatic space as, e.g. enterobactin (Sect. 2.7). Alternatively Fe3+
is transferred at the cell surface from the ferri-siderophore to a trans-membrane
transport system (“taxi mechanism”). A probably archaic and unspecific variety
of the taxi mechanism comprises the reduction of Fe3+ at the cell surface (see
ferrichrome A, Sect. 2.6 (99, 105)). The terms “shuttle” and “taxi mechanism” were
coined by Raymond and Carrano (296).
A microbial strain may produce more than one siderophore. There are varia-
tions in fatty acid chains of a lipophilic part or in the amino acids making up the
backbone, as well as released intermediates of the biosynthetic chain. These
variations belong all to the same structural pattern. However, there is also the
possibility that so-called secondary siderophores are encountered. They constitute
a different structural type, usually less complex in their constitution but also less
efficient in binding Fe3+ than the primary ones. Secondary siderophores will be
produced when the demand for iron is not so severe or in case there is a genetic
defect impeding the production of the primary ones. Examples will be found
throughout the review.
Microbial Siderophores 3

Obviously siderophores can be potent virulence factors of pathogenic bacteria.

Siderophores in many cases have elaborate structures providing recognition only by
the receptor site of the producing species. This renders a pirating by competing
microorganisms more difficult. The structural specificities of siderophores have
been used for classification purposes of bacterial species (see especially pyoverdins,
Sect. 2.1).
Whether a Fe3+ binding metabolite is actually involved in the iron transport has
not always been established firmly. Criteria are the pronounced production under
iron starvation and growth after feeding, or labeling studies (at best simultaneously
of Fe3+ and of the ligand, see, e.g. parabactin, Sect. 3.2, and schizokinen, Sect. 4.1).
Chelators whose function is uncertain will be included in this review with an
explanatory remark. Incompletely characterized siderophores will be mentioned
when at least some structural elements have been identified. However, the mere
statement that color reactions for catecholates (8a) or hydroxamates (9a) were
positive will not be sufficient. Not included will be the sideromycins, conjugates
of siderophores with antibiotically active residues, produced mainly by Streptomy-
ces spp., which use the iron transport paths for “Trojan Horse” strategies. For
further references see (34, 97, 187).
Due to its high charge density, small ion radius, and low polarizability, Fe3+ is a
hard Lewis acid and can bind strongly to hard Lewis bases such as oxide ions. It
forms octahedral d5 high spin complexes providing six coordination sites, which
can accommodate three bidentate ligands. The major ligands types are catecholates,
hydroxamates, and a-hydroxy carboxylates; other ligands are encountered occa-
sionally. Siderophores containing different ligand types are not uncommon. Three
bidentate ligands are often connected by aliphatic segments keeping them in place
for complexation. This results in an entropic advantage over three non-connected
ligands. Siderophores containing only two binding sites form either (Fe3+)2Lig3
complexes or the remaining two octahedral loci accommodate some external ligand
(see, e.g. pyochelin, Sect. 5). For (Fe3+)2Lig3 structures with three bridges or with
one bridging ligand have been discussed. The latter variety has been proven for
alcaligin (Sect. 3.3). Three bidentate ligands can be arranged around the Fe3+
nucleus in two ways forming a left-handed or a right-handed screw, designated
as L or D. Three identical ligands can point all in the same direction (cis) or one
of them is reversed (trans). The chiral arrangement of the Fe3+ complex can be
determined by X-ray analysis or can be deduced from the sign of the broad CD
extremum at ca. 500 nm correlated with the metal-to-ligand charge transfer band.
A positive De indicates a L configuration.
Ga3+ complexes are frequently analyzed for two reasons. Ga3+ also forms
octahedral structures and it has almost the same ion radius as Fe3+ (62 vs. 65 pm).
In contrast to Fe3+ it is diamagnetic and its complexes are therefore amenable to
NMR analysis. Also in contrast to Fe3+ it cannot be reduced and therefore it is used
for uptake studies interested in the fate of the complex in the cell.
Siderophores can be classified by different criteria. In this review related struc-
tural types will be grouped together. Some arbitrariness cannot be avoided due to
the occurrence of “mixed types”. Cross-references will then be given. Trivial names
4 H. Budzikiewicz

have either been given to the free ligands or to their iron complexes. In the latter
case the free ligands are referred to as “desferri” or “deferri” (sometimes in a
shortened form as “desferrioxamines” for “desferriferrioxamines”) or as “pro” (see
Sect. 3.3). Occasionally the name applied originally to the iron complex was used
later for the free ligand (e.g. ferribactins, Sect. 2.1). These variations should be kept
in mind when literature search programs are used.
For earlier compilations of siderophores see (97, 255a, 276), specifically for
fungal siderophores (157a, 300, 383), and for biosynthesis pathways (19, 63, 403).
Reviews for specific classes of siderophores will be mentioned where applicable.

2. Peptide Siderophores

In this group the ligands are incorporated in a peptide chain usually containing
both D- (underlined in the structural formulas below) and L-configured amino acids.
Frequently the two ends of the peptide chain are blocked by the formation of cyclic
structures or otherwise. This prevents the degradation by proteolytic enzymes. Non-
proteinogenic amino acids are encountered (homoserine, Hse; ornithine, Orn; 2,4-
diaminobutyric acid, Dab; 2,3-dehydrobutyric acid, Dhb), lysine and ornithine may
be incorporated in the chain by their e/d- rather than by their a-amino group, and
amino acids may be modified to form ligand sites (3-hydroxy-aspartic acid,
OHAsp; 3-hydroxy-histidine, OHHis; N5-acyl-N5-hydroxy-ornithine, acylOHOrn;
N-hydroxy-cyclo-ornithine, i.e. 3-amino-1-hydroxy-piperidone-2, cOHOrn). Dia-
minobutyric acid frequently condenses with the preceding amino acid (Chart 1)
giving a tetrahydropyrimidine ring (116). These condensation products are indi-
cated below by a parenthesis as e.g. (Hse-Dab) in azoverdin (Sect. 2.2).

2.1. Pyoverdins and Related Siderophores from

Pseudomonas spp.

The most thoroughly investigated representatives are the pyoverdins, also spelled
pyoverdines and occasionally named pseudobactins (353), produced by the fluores-
cent members of the genus Pseudomonas. For reviews see (44, 231); for a detailed

HNOC HNOC

R NH NH2 HN N

HN O
R NH

Chart 1. Condensation of a Dab residue with the preceding amino acid residue
Microbial Siderophores 5

a b COOH
HOOC
1

HO N NH HO N NH
5
HO 6 NH2 HO NH2

c d
HOOC HOOC

HO HN NH HO N N
CO
NH2 HO N
H

Fig. 1. Chromophore types: (a) pyoverdin, (b) isopyoverdin, (c) ferribactin, (d) azotobactin

study of the siderophores of this genus (37). Pyoverdins consist of three distinct
structural parts, a chromophore (Chra) (Fig. 1, a), a peptide chain comprising six to
twelve amino acids, and a dicarboxylic acid (succinic acid – Suc-, malic, glutamic,
and 2-oxoglutaric acid) or monoamides (succinamide, malamide). For glutamic and
2-oxoglutaric acid the binding to the chromophore by their g-carboxyl groups has
been established by chemical degradation (124). For malic acid some not really
convincing and partially contradictory NMR arguments have been advanced (319)
for the binding by the carboxyl group neighboring the CH2 group. Recently mass
spectrometric arguments were reported suggesting a binding via the other carboxyl
group (45).
The about fifty pyoverdins for which structures have been proposed can be
divided into three structural types exemplified by the three pyoverdins of Pseudo-
monas aeruginosa (234) (Fig. 2), viz. pyoverdins (a) with a C-terminal tri- or
tetra-cyclopeptidic substructure (lactam formation between the C-terminal car-
boxyl group and an in-chain lysine or ornithine), e.g. ATCC 15692 (PAO1) (1),
(b) with a C-terminal cOHOrn, e.g. ATCC 27853 (2), and (c) with a C-terminal
free carboxyl group, e.g. Pa6 (R) (3). The free carboxyl group is probably the
hydrolysis product of a depsipeptidic substructure (ester formation between the
C-terminal carboxyl group and an in-chain serine or threonine). In several cases
both the cyclic and the hydrolyzed open-chain form were found (e.g. (50)). Binding
sites for Fe3+ are the catecholate part of the chromophore Chra and two units in the
peptide chain, hydroxamate (acylOHOrn, cOHOrn) and/or a-hydroxycarboxylate
(OHAsp, OHHis).
Complete structural analysis requires mass spectral and NMR data as well as
chemical degradation and analysis of the chirality of the constituent amino acids,
determination of the mode of linkage of lysine (a- or e-), the size of the cyclopep-
tide or cyclodepsipeptide ring, etc. (37). In some cases structures have been
proposed based only on mass spectral data. Difficulties arising in this approach
were discussed (44). To determine the three-dimensional structure an X-ray
6 H. Budzikiewicz

D-Ser L-Arg
NH
O
OH NH
HN H2 N
NH
O O
D-Ser
NH
L-Lys L-(CHO)OHOrn OH
O NH
CH2 CH2 O
H2 C CH2 NH H N H
HN OH

O
O HO N NH ATCC 15692 (PAO1) (1)
O
HO NH OH HO NHR
L-Thr HN N O
NH H
O O
L-(CHO)OHOrn
OH
L-Thr

L-Orn NH2

O D-(CHO)OHOrn
O
Gly HN
HN O
HN
H2 C OH
O
D-Ser
NH
HN
HO O
D-aThr H N H
OH
H3 C HO N NH
O O
HN
ATCC 27853 (2) O HO NHR
HO OH
HN N
O
L-Ser L-cOHOrn

L-(CHO)OHOrn L-Dab
L-Gln
O O O N
OH
NH D-Ser
HN N
H2 N H NH
O H O
H
N O
HN
O OH HO N NH
D-Gln
H2 N
OH HO NHR
O
HN N O
CH2 R (Pa6) (3)
CH2 CH2 H
HN
O
HOOC D-(CHO)OHOrn
Gly

Fig. 2. Pyoverdins from Pseudomonas aeruginosa representing the three structural types

analysis (Plate 1) so far only of the Fe3+ complex of the pyoverdin B10 (4) was
performed (353).

4 Suc-Chra-eLys-OHAsp-Ala-aThr-Ala-cOHOrn
 Microbial Siderophores

Plate 1. X-ray structure (stereo view) of ferri-pyoverdin B10 (ferri-4)

7
8 H. Budzikiewicz

Plate 2. Calculated three-dimensional structure of the Ga3+-complex of pyoverdin PL8 (without

side chain) Chra-Lys-acetylOHOrn-Ala-Gly-aThr-Ser-cOHOrn

As an alternative strategy the investigation of the isomorphic Ga3+ complexes by

NMR analysis was developed (241) for the pyoverdin GM-II (5) and extended to
other pyoverdins, e.g. PL8 (16) (Plate 2) (H. Budzikiewicz, unpublished).

5 Suc-Chra-Ala-Lys-Gly-Gly-OHAsp-Gln-Ser
-Ala-Ala-Ala-Ala-cOHOrn

In all cases the metal ion was found to lie at the surface of the complex. This
facilitates its uptake and release. For the pyoverdins both L and D arrangements
have been reported (37).
Iron transport through the cell membrane follows a modified shuttle mechanism.
Evidence has been presented that the iron-free siderophore of P. aeruginosa PAO1
(1, Fig. 2) binds strongly to the receptor protein (67, 314a). This suggests two
scenarios for the subsequent steps of iron transfer, an exchange of the ligands or a
transfer or Fe3+ between them. By 3H- and 55Fe-labeling as well as fluorescence
studies it was shown that an exchange between the approching ferri-pyoverdin and
the bound iron-free pyoverdin occurs and that the former one enters the cell, i.e. that
no Fe3+ exchange between the two ligands takes place (314b). Model studies with
Aeromonas (Sect. 2.7) demonstrated there the iron-exchange variety. Binding of the
iron-free siderophore to the receptor protein seems to be a common feature of the
transport systems of P. aeruginosa and Escherichia coli (145a).
Microbial Siderophores 9

The peptide chains of the pyoverdins are responsible for the recognition of the
ferri-siderophore at the cell surface of the producing species. It is usually highly
strain specific. Cross-recognition between two strains is only observed when struc-
turally closely related pyoverdins are produced (125, 233). An exception seems to
be P. aeruginosa ATCC 15692, which besides its own ferripyoverdin (Fe-1),
accepts several foreign ones (128a).
Without going into structural details, the pyoverdins stemming from the sapro-
phytic group Pseudomonas aeruginosa/fluorescens/putida contain either two
hydroxamic acid units or one hydroxamic and one a-hydroxycarboxylic acid, and
those from the phytopathogens P. syringae etc. two a-hydroxycarboxylic acids.
Structural differences of pyoverdins have been used recently to characterize species
newly defined by breaking up the classical cluster of P. fluorescens/putida (e.g.
(229, 231)). A listing of all pyoverdins from Pseudomonas spp. for which structural
data have been published up to December 2009 is contained in the Appendix.
Pyoverdin-like siderophores with other chromophores have also been observed
(see Fig. 1) (45). The 5,6-dihydropyoverdins (Chra without the 5,6-double bond)
and the ferribactins (Chrc) are considered to be biogenetic precursors of the
pyoverdins (318) (the term “ferribactin” was originally used for the Fe3+ complex
(221) and later for the free ligand). An azotobactin chromophore (Chrd, see also
below Sect. 2.2) is occasionally found in Pseudomonas isolates (e.g. (146)). Side-
rophores produced by a specific Pseudomonas strain but differing in the chromo-
phore always have identical peptide chains.
Isopyoverdins contain the siderophore Fig. 1, Chrb with aspartic acid as the first
amino acid. They have been encountered so far only in isolates from Pseudomonas
putida strains, e.g. BTP1 (168) (6).

6 Glu-Chrb-Asp-Ala-Asp-acetylOHOrn-Ser-cOHOrn

2.2. Azomonas and Azotobacter Siderophores

For a detailed discussion of this class of compounds see (37).

Azomonas macrozytogenes produces a siderophore with an isopyoverdin chromo-
phore, azoverdin, but with a peptide chain 7 related to those of azotobactins, viz. (236).

7 Suc-Chrb-Hse-(Hse-Dab)-acetylOHOrn-Ser-acetylOHOrn

The three-dimensional structure of the Ga3+ complex was determined by NMR

techniques as outlined above. Also here the metal ion lies at the surface of the
complex (377).
From Azotobacter vinelandii the structures of two siderophores were elucidated.
They contain the chromophore Chrd (Fig. 1) and Hse units: azotobactin 87-I (8)
(from the three Hse in this sequence two are L and one D configured) from the strain
ATCC 12837 (314), and azotobactin D (9) (76) from the strain CCM 289.
10 H. Budzikiewicz

8 Chrd-Ser-Ser-Hse-Gly-OHAsp-Hse-Hse-Hse
-b-hydroxybutyrylOHOrn-Hse

9 Chrd-Asp-Ser-Hse-Gly-OHAsp-Ser-Cit-Hse-acetylOHOrn-Hse

Both of them are accompanied by compounds where the C-terminal Hse forms
a g-lactone ring (azotobactin 87-II and d). An azotobactin O for which also a
structure had been proposed (120) was shown later to be identical with azoto-
bactin D (272). For secondary metabolites see protochelin and its constituents
(Sect. 3.2).
Azotobacter chroococcum produces ornithine-containing hydroxamate sidero-
phores with molecular masses 800 and 844 Da (difference of one carboxyl group?)
of unknown structure (115a).

2.3. Anachelin

Cyanobacteria were probably the first organisms to perform oxygenic photosynthe-

sis resulting eventually in the oxidation of environmental Fe2+ to Fe3+ with all its
consequences. To cope with this problem the production of siderophores was
initiated. Not much is known about the siderophores of cyanobacteria. Schizokinen
(see below under citrate siderophores, Sect. 4.1) (326) found to be produced by
several bacterial species may have been acquired by gene transfer; see however also
the citrate siderophores synechobactins.
Certainly of genuine origin is anachelin, a strange compound whose biosynthe-
sis requires inter alia steps from the peptide and polyketide paths. It exists in
an open (anachelin H, Fig. 3, (10)) and two cyclic forms arising from an interaction
of the carbonyl group of the salicylic acid residue with one of the neighboring

OH HO
OH OH OH O H O H
N N
N N N
HN O H O H
O
OH
OH
10
OH
OH

OH OH
OH
HO O OH
N
N
O
11 HO 12

Fig. 3. Anachelin H (10), anachelin 1 (11), anachelin 2 (12)

Microbial Siderophores 11

hydroxy groups (anachelin 1 and 2, Fig. 3, (11) and (12)) (22, 167). The relative
and absolute stereochemistry of all chiral centers was established (22, 166) and
confirmed by synthesis (121) (see Sect. 8.1). In solution anachelin forms a b-turn
arrangement (122). Mass spectrometric analysis of the Fe3+ complex suggests a
1:1 ratio.

2.4. Actinomycetal Metabolites

Desferrimaduraferrin is a Fe3+ complexing metabolite of Actinomadura madurae

(185). It consists of salicylic acid, b-Ala, Gly, L-Ser and N5-hydroxy-N2-methyl-L-
Orn, with the latter incorporated in a heterocyclic system (Fig. 4, 13). From the
same species the madurastatin group was obtained (136). The main representative
A1 shows the sequence salicylic acid, D-azaridine carboxylic acid, L-Ala, b-Ala,
N5-hydroxy-N2-methyl-Orn, L-cOHOrn (Fig. 4, 14). In A2 the azaridine ring is
opened giving a Ser residue, A3 is an isomer of the open form with the salicylic acid
bound to the hydroxy group of Ser. B1 and B2 are the precursors N-salicyloyl-
azaridine carboxylic acid and N-salicyloyl-Ser. The madurastatin species A1 forms
a 1:1 Fe3+ complex as shown by mass spectrometry.
Asterobactin from Nocardia asteroides (257) contains salicylic, 2,3-dihydroxy-
propionic, and 2-methyl-3-hydroxyundecanoic acid as well as derivatized Orn and
Arg residues (Fig. 4, 15). It forms a Fe3+ complex. The stereochemistry of the
various centers was not determined but L-configuration is proposed for Orn and Arg
for biosynthetic reasons (general amino acid pool) and a negative [a]D25 of astero-
bactin. Whether the three compounds are involved in metal transport has not been
investigated.

O O H O O H
N N
N N N N
H H OH
O N
OH 13 HO
O

O O OH NH O
H H
N N N OH
N N N
H
O O O
OH 14

(CH2)3N(OH)CHO
O O H
O N CO-NHOH
O N
H
OH O C8H17O (CH2)3N(OH)-C(NH2)=NH
OH 15

Fig. 4. Desferrimaduraferrin (13), madurastatin A1 (14), asterobactin (15)

12 H. Budzikiewicz

2.5. Bacterial Hydroxamate Siderophores

Exochelins (322, 323) are peptidic siderophores from Mycobacterium spp. (see also
below mycobactins). Exochelin MS (16) from M. smegmatis comprises b-Ala and
three N5-OHOrn units, which are linked by their N5 atoms to acyl groups thus
forming hydroxamic acids.

16 N 5 -formyl-N 5 -OHOrn-b-Ala-N 5 -OHOrn-aThr-N 5 -OHOrn

Exochelin MN (17) from M. neoaurum contains N2-methyl-N5-hydroxy-Orn

linked by its N5 to b-Ala and by its carboxyl group to N2 of Orn, which in turn is
bound amidically to cOHOrn; all amino acids are L configured.

17 OHHis-b-Ala-b-Ala-MeOHOrn-Orn-cOHOrn

The Fe3+ chelating properties of exochelin MN (17) were investigated in detail

(pKa values, chelation constants, redox equilibria, etc.) (87). In one publication
(128) siderophores from Mycobacterium tuberculosis otherwise referred to as
carboxymycobactins (see below Sect. 2.8) were also named exochelins.
Vicibactin (18) (previously called hydroxamate K (61a)) from Rhizobium legu-
minosarum is a macrocyclic trilactone consisting of N2-acetyl-N5-hydroxy-D-Orn
and (R)-3-hydroxybutyric acid (91).

18 ½-O-CH(CH3 )-CH2 -CO-NOH-(CH2 )3 -CH(NHCOCH3 )-CO-3

Vicibactin 7101 from a mutant strain lacks the N-acetyl groups but shows
comparable siderophore activity as demonstrated by 55Fe3+ uptake studies (91).
The answer to the question why vicibactin is biosynthesized if vicibactin 7101 is as
efficient in iron sequestering may be the greater stability of the acetylated com-
pound (cf. fusarinines, Sect. 2.6). Vicibactin is identical with neurosporin produced
by the fungus Neurospora crassa for which X-ray data of the Fe3+ complex are
available. CD spectroscopy indicates a L-cis configuration both for crystals and for
solution (108).
A hydroxamate siderophore from Salmonella typhimurium is described as con-
taining isoleucine/leucine, phenylalanine and valine, but not serine and lysine.
Further details are not given (290a). For other Salmonella siderophores see
Sect. 2.7.

2.6. Fungal L-Ornithine-Based Hydroxamate Siderophores

For other fungal siderophores see neurosporin above, pistilarin (a spermidine

derivative, Sect. 3.2) and rhizoferrin (a citrate siderophore, Sect. 4.4); siderophores
Microbial Siderophores 13

produced by marine fungi are treated in (147). The siderophores to be discussed

here can be divided in three groups, the fusarinines, the ferrichromes, and the
coprogens, all based on N5-hydroxy-N5-acyl-L-Orn. There exist some earlier
reviews (204, 300, 383); for the early days see also (395). Lists of sidrophores
and the producing fungi have been assembled (384, 385) to which the marine yeast
Aureobasidium pullulans may be added (374a); see also (139). Chromatographic
separation techniques were established (175, 192). For a number of siderophores
and their Fe3+ complexes X-ray and other structural analyses are reported (366). In
the text and the figures, the desferri ligands will be presented without adding the
prefix “desferri” to their names.
Fusarinines (19) produced by several fungal genera comprise the acyl unit (Z)-5-
hydroxy-3-methyl-pent-2-enoic acid (anhydromevalonic acid) (Fig. 5, a) bound to
N5-hydroxy-L-ornithine. They can be a linear monomer, dimer (fusarinine A) or
trimer (fusarinine B) (the monomer can also be (E)-configured) (172). Fusarinine B
is possibly identical with coprogen C (89).

19 HO-[CO-CHNH2 -(CH2 )3 -NOH-CO-CH = CCH3 -(CH2 )2 -O]1
3 -H

The trimer by forming an ester bond between the two terminal functions results
in a lactone ring (fusarinine C or fusigen) (88, 313). Since the fusarinines are rather
labile it is not clear whether the open forms are genuine siderophores, precursors of
fusigen or just hydrolysis products (204). The monomers (Z)- and (E)-fusarinine
form in aqueous solution at neutral pH (Fe3+)Lig3 complexes, which are mixtures of
L and D isomers (172).
The free a-amino groups of the ornithine units were also found in an acetylated
form (90, 243). Since triacetylfusigen is resistant to hydrolysis, formation of the
acetylated mono-, di-, and trimeric linear acetylfusarinines is assumed to be
effected by enzymatic cleavage (103a, 243). X-ray and CD data of the Fe3+
complex of triacetylfusigen have been obtained (152). Depending on the solvent
used for crystallization the crystals show L-cis or D-cis configuration, while in
solution D-cis prevails.
The members of the ferrichrome group are cyclohexapeptides with the general
structure [-(N5-acyl-N5-hydroxy-L-Orn)3-A-B-Gly-] where A and B can be Gly,
Ala, or Ser (Table 1); the various acyl groups are depicted in Fig. 5. Exceptions are
tetraglycylferrichrome, a cycloheptapeptide with four Gly units in sequence and
three acetyl residues in the Orn part (ferrichrome with an additional Gly) (82), and
des(diserylglycyl)ferrirhodin, a linear tripeptide containing only the three Orn units

a. (Z)-CO-CH=CCH3-(CH2)2-OH f. (E)-CO-CH=CCH3-CH2-COOH
b. (E)-CO-CH=CCH3-(CH2)2-OH g. CO-CH2-COOH
c. (E)-CO-CH=CCH3-CHOH-CH2OH h. CO-(CH2)14-CH3
d. (E)-CO-CH=CCH3-(CH2)2-OCOCH3 i. COCH3
e. CO-CH2-CH(CH3)OH-(CH2)2-OH

Fig. 5. Acyl residues encountered in fungal hydroxamate siderophores

14 H. Budzikiewicz

Table 1. The ferrichrome familya

~NH-CH-CO-NH-CH-CO-NH-CH-CO-A-B-Gly~
(CH3)3 (CH2)3 (CH2)3
N N N
HO Ac HO Ac2
1
HO Ac3

Name A B Ac1 Ac2 Ac3 References

ferrichrome Gly Gly i i i (106)
ferrichrome A Ser Ser f f f (106, 383, 396)
ferrichrome C Gly Ala i i i (209, 383)
ferrichrysin Ser Ser i i i (170, 174, 184, 383)
ferricrocin Gly Ser i i i (184, 383)
ferrirubin Ser Ser b b b (170, 174, 383)
ferrirhodin Ser Ser a a a (383)
malonichrome (Gly Ala) g g g (104)
sake colorant A Ser Ala i i i (209)
asperochrome A Ser Ala b b b (155, 174)
asperochrome B1 Ser Ser i b b (170, 174)
asperochrome B2 Ser Ser b (b i) (170, 174)
asperochrome B3 Ser Ser b (b i) (170)
asperochrome C Ser Ser (b b d) (174)
asperochrome D1 Ser Ser b i i (170, 174)
asperochrome D2 Ser Ser i (b i) (170, 174)
asperochrome D3 Ser Ser i (b i) (170, 174)
asperochrome E Ser Ser (a b b) (177)
asperochrome F1 Ser Ser (b b e) (177)
asperochrome F2 Ser Ser (b b e) (177)
asperochrome F3 Ser Ser (b b e) (177)
a
Parentheses indicate that the position of the residues is not certain. For the designation of the acyl
residues see Fig. 5. Where the chirality of Ala or Ser was determined it was found to be L

of ferrirhodin (169). One of the members of this group, ferricrocin was identified as
an intra- and intercellular iron transporter for Aspergillus fumigatus (374).
Ferrichrome (as do also at least the members of the group for which structural
data are available ((366) and references noted in Table 1) shows L-, synthetic
enantio-ferrichrome based on D-Orn D-configuration (253). Uptake studies per-
formed with Ustilago sphaerogena (103) using 59Fe3+ and [14C]-ferrichrome under
optimal conditions (30 C, pH 7) showed rapid resorption of both labels during the
first 30 min. The uptake of 59Fe3+ continued for further 30 min, then the level of
radioactivity stayed constant, while the level of 14C dropped to a lower constant
value. Desferri-[14C]-ferrichrome is not taken up or even bound to the cell surface.
These findings are in agreement with shuttle mechanism and re-export of the ligand
after detachment of iron. See also analogous experiments with parabactin (Sect. 3.2)
and with schizokinen (Sect. 4.1). In contrast, ferrichrome A does not enter the cell.
Fe3+ is rather reduced and given off at the cell surface and subsequently transported
into the cell (99, 105). 55Fe uptake studies performed with Neurospora crassa
showed the same incorporation rate for ferrichrome and tetraglycylferrichrome
indicating that the peptide ring size is of minor importance for the acceptance by
the transport system (82).
Microbial Siderophores 15

The third group comprises the coprogen family. Their characteristic element is a
diketopiperazine ring formed by the head-to-head condensation of two N5-acyl-N5-
hydroxy-L-Orn units. Rhodotorulic acid (20) first isolated from the yeast Rhodoto-
rula pilimanae and subsequently found to be produced by many yeasts (9a) contains
two acetyl groups (Fig. 6) (9), and dimerum acid (21) from Fusarium dimerum (89)
and other fungi (172) two (E)-anhydromevalonyl residues (Fig. 6). An acetyl-
dimerum acid of unknown structure has been encountered (157b). In the coprogens
a third variously substituted (E)-fusarinine unit is added by means of an ester bond
(Table 2) (300). Rhodotorulic and dimerum acid form (Fe3+)2Lig3 complexes, but
also a mixed 1:1:1 complex of Fe3+ with dimerum acid and (Z)-fusarinine was
observed. Various coprogens were shown to yield 1:1 complexes with Fe3+ (60,
153, 172). The CD-spectra of the coprogen and neocoprogen I/II Fe3+ complexes
demonstrate D-configuration for the solutions and for the crystals of neocoprogen I

H
O N
NOH-Ac

Ac-HON
N O
H

Fig. 6. Rhodotorulic acid (Ac = Fig. 5, i) (20) and dimerum acid (Ac = Fig. 5, b) (21)

Table 2. The coprogen familya,b

H
O N (CH2)3-NOH-Ac2

Ac1-NOH-(CH2)3 N O
H

Ac2 = CO-CH=C(CH3)-(CH2)2-O-CO-CH(NR1R2)-(CH2)3-NOH-Ac3

Name Ac1 Ac3 R1 R2 References

coprogen b b COCH3 H (117, 184a)
coprogen B b b H H (89)
triornicin (isoneocoprogen I) b i COCH3 H (117)
isotriornicin (neocoprogen I) i b COCH3 H (118, 153)
neocoprogen II i i COCH3 H (153)
N2-methyl coprogen B b b CH3 H (30c, 157b)
N2-dimethyl coprogen b b CH3 CH3 (173)
N2-dimethyl neocoprogen I i b CH3 CH3 (173)
N2-dimethyl isoneocoprogen I b i CH3 CH3 (173)
hydroxycoprogen b c COCH3 H (176)
hydroxyneocoprogen I i c COCH3 H (176)
hydroxyisoneocoprogen I c i COCH3 H (176)
palmitoylcoprogen b b h H (5)
a
For the designation of the acyl residues see Fig. 5
b
Coprogen C is possibly identical with fusarinine B (89)
16 H. Budzikiewicz

(153). Palmitoylcoprogen (Table 2 last entry) from Trichoderma spp. is retained in

the fungal mycelium and may therefore be considered as a candidate for an iron
uptake taxi mechanism (5).
Relationships between the structure of the siderophores and the iron transport
were investigated for the fungus Neurospora crassa (160, 160a). Apparently two
different receptors exist for ferrichromes and for coprogenes. For the recognition
and the binding to the cell surface the iron configuration and the nature of the acyl
chains is of importance. However, the transport system seems to be the same for
both siderophore types dependent on the peptide part of the molecules.

2.7. Catecholate Siderophores

For other catecholate siderophores see di-/tri-aminoalkane (Sect. 3.2) and citric acid
(Sect. 4.3) derivatives below; for a review see (38).
2,3-Dihydroxybenzoic acid is produced by a series of microorganisms, viz.
Aerobacter aerogenes (291), Azotobacter vinelandii (70, 273), Bacillus subtilis
(282), Escherichia coli (261, 291), Klebsiella oxytoca (196), Micrococcus denitri-
ficans (347), Nocardia asteroides (112), Rhizobium sp. (74), and Salmonella typhi-
murium (290), 3,4-dihydroxybenzoic acid by a mutant of Aerobacter aerogenes
(291), Azomonas macrocytogenes (380), Bacillus anthracis (123), Escherichia coli
(291), Magnetospirillum magneticum (54), and Mycobacterium smegmatis (291).
Both dihydroxybenzoic acids can act as siderophores.
Condensation products of DHB (which usually is found also in the fermentation
broth) with amino acids were reported, viz. with glycine from Bacillus subtilis (164)
named subsequently itoic acid (282); with serine from Escherichia coli (261) and
Klebsiella oxytoca (196); with threonine from Klebsiella oxytoca (196) and Rhizo-
bium spp. (275, 327); with arginine from Pseudomonas stutzeri (62); with glycine
and threonine from Rhizobium sp. (240); with threonine and lysine as well as
with leucine and lysine from Azospirillum lipoferum (312, 320). In most cases the
isolate (sometimes designated as being a siderophore) was hydrolyzed and the
constituents were determined by paper chromatography. The relative amounts of
the constituents, the chiralities of the amino acids and the molecular mass of the
isolate have not been determined. Hence it is not known whether condensation
products of the enterobactin type exist.
Ideally suited for Fe3+ complexation – exemplified by the extremely high
complexing constant of 1049 (originally estimated as 1052) (210) – is enterobactin
(enterochelin) first isolated from Salmonella typhimurium (286) and Escherichia
coli as well as from Aerobacter aerogenes (261) and recently from Enterobacter
cloacae (368). It is a cyclic trilactone of N-2,3-dihydroxybenzoyl-L-serine
(DHB-Ser) (Fig. 7, 22). Syntheses have been reported (71, 321). DHB-Ser by itself
can act as a siderophore. In the culture medium degradation products of enter-
obactin also were found, and are open-chain compounds comprising two or
three constitutional units. Iron release in the cell is effected by degradation of
Microbial Siderophores 17

O
OH
NH OH
O
OH O O O
OH
O
HN NH O
R O
O HO
22, R = H
HO
CH2OH
23, R = HO O
HO
OH O
OH
NH-CO-CH2-NH OH
O

OH O O O
OH
O
NH-CH2-CO-NH N-CO-CH2-NH
O
O
O 24 HO

HO

Fig. 7. Enterobactin (22), salmochelin S4 (23), corynebactin (24)

enterobactin. Ferri-enterobactin shows a D-cis configuration, with the synthetic

ferri-enantio-enterobactin based on D-Ser L-cis-configuration (256).
Escherichia coli and Salmonella enterica produce a derivative of enterobactin,
salmochelin S4, where two of the aromatic rings are b-C-glucosylated in the
5-position (Fig. 7, 23). Also glycosylated degradation products or precursors (mono-
mer: salmochelin SX, dimers: S1 and S5, linear trimer: S2) could be isolated (31,
135, 247). Salmochelin S4 is identical with pacifarin, a compound active against
salmonellosis (378), and SX with pacifarinic acid, glucosylated DHB-serine (247).
From Corynebacterium glutamicum the siderophore corynebactin was obtained
(41). It differs from enterobactin in being composed of three DHB-Gly-L-Thr units
(Fig. 7, 24). Later the same siderophore was found to be produced also by Bacillus
subtilis and named bacillibactin (223). Its complexation constant is ~1048 (84). The
monomeric unit DHB-Gly-Thr was isolated from Bacillus licheniformis (357a).
Azospirillum brasilense under iron starvation produces spirilobactin. Hydrolysis
yields DHB, ornithine, and serine of unknown chirality in a ratio of 1:1:1. The
molecular mass was not determined and hence it is not known whether spirilobactin
forms a (cyclic) trimer. Iron uptake was studied with the 59Fe3+ complex (10).
Erwinia chrysanthemi (278) and Serratia marcenscens (101) produce N2-DHB-
D-Lys-L-Ser named chrysobactin. The structure was confirmed by synthesis. At
physiological pH values 2 or 3 chrysobactin residues are associated with Fe3+ (280).
18 H. Budzikiewicz

From Chryseomonas luteola in addition to chrysobactin a derivative (chrysomonin)

was isolated where C-6 of the DHB unit is substituted with the N-atom of a
pyridinium cation. Chrysomonin could be synthesized from chrysobactin (1a).
Amonabactins (25) were found to be excreted by Aeromonas hydrophila (355,
356) and by Pseudomonas stutzeri (398). They are based on the peptides Lys-Lys-
Phe and Lys-Lys-Trp; N6 of the first L-Lys residues is derivatized by DHB or by a
DHB-Gly residue, and that of the second L-Lys by a DHB group (Table 3). At high
pH values and excess ligand a (Fe3+)2Lig3 complex is formed, while at neutral pH a
1:1 ratio prevails with H2O molecules satisfying the remaining coordination sites.
The 2:3 complex is preferentially D-configured, and the 1:1 complex is achiral (357).
Model uptake studies with Aeromonas were performed with 55Fe3+ and a 14C-labeled
artificial synthetic siderophore. They demonstrate a modified shuttle mechanism. An
iron-free siderophore molecule is strongly bound to the receptor protein and Fe3+
exchange occurs between an approaching ferri-siderophore and the bound one, which
then is transported into the cell (337); cf. the pyoverdins (Sect. 2.1).
Alterobactin A is a cyclodepsipeptide from Alteromonas luteoviolacea, with
N8-DHB-(4S),8-diamino-(3R)-hydroxy-octanolyl-D-Ser-Gly-L-Arg-L-threo-3-hydroxy-
Asp-Gly-L-threo-3-hydroxy-Asp having an ester bond between the C-terminal
carboxyl group and Ser. It is accompanied by its hydrolysis product alterobactin
B (Fig. 8, 26, 27) (298). Alterobactin A forms a 1:1 complex with Fe3+ with an

Table 3. Amonabactins (25)

R1 -NH-ðCH2 Þ4 -CHðNH2 Þ-CO-NH-CHðCOR2 Þ-ðCH2 Þ4 -NH-DHB

Name R1 R2
Amo T 789 DHB-Gly D-Trp
Amo P 750 DHB-Gly D-Phe
Amo T 732 DHB D-Trp
Amo P 693 DHB D-Phe

OH

OH OH ( )

CO-NH-(CH2 )4-CH-CH-CH2-CO-Ser-Gly-Arg-b-OHAsp-Gly-b-OHAsp
NH2

26: with ester bond between OHAsp and Ser

27: without ester bond between OHAsp and Ser

SO3 H
OH

OH OH
CO-NH-(CH2 )4-CH-CH-CH2-CO-Asn-b-OHAsp-Lys-X-b-OHAsp-Gly
NH2

28: X = Lys, 29: X = Arg

Fig. 8. Alterobactins (26, 27), pseudoalterobactins (28, 29)

Microbial Siderophores 19

unexpectedly high complexing constant (between 1049 and 1053), higher than that
of enterobactin above, despite the fact that two complexing sites are a-hydroxy
acids which bind Fe3+ less efficiently than DHB units (148). A synthesis has been
reported (83) (see Sect. 8.2).
Related structures are the pseudoalterobactins A and B from Pseudoalteromonas
sp. (Fig. 8, 28, 29) (183), one of the rare examples of bacterial metabolites containing
an aromatic sulfonic acid (40). Chiralities of the constituents were not determined.
Heterobactin A and B (30) are produced by Rhodococcus erythropolis (59).
They are based on the sequence Orn-Gly-cOHOrn. The N5-amino group of Orn is
substituted by a DHB group. In heterobactin B, the a-amino group of Orn is free
(R = H); in heterobactin A, R is probably a 2-hydroxybenzoxazolyl-carbonyl group.

30 DHB-NH-(CH2 )3 -CH(NHR)-CO-NH-CH2 -CO-cOHOrn

Rhodobactin (31) was isolated from Rhodococcus rhodochrous (86). A sequence

of four Orn units derivatized in different ways is linked together. The nitrogen
atoms of the N-terminal Orn are substituted with DHB groups, the N-terminal Orn
is followed by two Orn moieties, for which the N5-amino groups are transformed
into urea units (NH2CONH-), and the C-terminus is cOHOrn. The stereochemistry
of the Orn units was not determined. Rhodobactin forms a 1:1 Fe3+/Lig complex.
Iron uptake was studied with 55Fe3+.

31 DHB-NH-ðCH2 Þ3 -CHðNH-DHBÞ-CO-ðNH-CH-COÞ2 -CO-cOHOrn

j
ðCH2 Þ3 -NH-CONH2

Thermobifida fusca, belonging to the Actinomycetales, produces three closely

related siderophores, namely, the fuscachelins (92). Fuscachelin B starts with the
sequence DHB-Arg-Gly-Gly-Ser, which is bound to the hydroxylated N5-amino
group of Orn. Its N2-amino group (the carboxyl group is free) is bound to the
C-terminus of the sequence Gly-Gly-Arg-DHB (32). Fuscachelin A is considered to
be the genuine metabolite, with B and C degradation products.

32 DHB-Arg-Gly-Gly-Ser-N5 -OHOrn-N2 H-Gly-Gly-Arg-N2 -DHB

In fuscachelin C the carboxyl group of Orn forms an amide, while in fuscachelin

A an ester bond occurs between the carboxyl group of Orn and the hydroxy group
of Ser.

2.8. Lipopeptidic Siderophores

From Burkholderia cepacia (formerly Pseudomonas cepacia) three siderophores

named ornibactins (33) were isolated for which the structures were determined by
20 H. Budzikiewicz

degradation and NMR studies (335, 336) as containing 3-hydroxy fatty acid
residues and putrescine that blocks the C-terminus, with acyl = R-CHOH-CH2-
CO (R = CH3, C3H7, C5H11).

33 acylOHOrn-OHAsp-Ser-formylOHOrn-NH-(CH2 )4 -NH2

The three ornibactins are accompanied by minor components, which contain an

additional oxygen atom. Their structure has not been investigated. Ornibactins are
the main siderophores of a series of Burkholderia strains accompanied in part by
pyochelin (Sect. 5) and cepabactin (Sect. 6) (235). A further B. cepacia siderophore
is cepaciachelin (Sect. 3.2) (15). The iron acquisition by the various siderophores of
B. cepacia has been discussed in detail (359).
From Nocardia strains several closely related compounds (nocobactins, formo-
bactin, amamistatins) were isolated that contain three typically Fe3+ binding sites,
two hydroxamate units, and a hydroxyphenyloxazole structure (cf. Sect. 3.2 below).
The C-terminus is N-hydroxy-cyclo-Lys bound to a long chain 3-hydroxy fatty acid,
whose hydroxy group is esterified by N6-acyl-N6-hydroxy-Lys, the a-amino group
of which is bound to 2-o-hydroxyphenyl-5-methyl-oxazole-4-carboxylic acid
(Table 4). For the amamistatins the configuration of the cyclic lysine was deter-
mined as L, the open one as D, and that of C-3 of the fatty acid as (S). The
involvement in the iron metabolism was not investigated.
Structurally related with the nocobactin family are the mycobactins and carboxy-
mycobactins (the latter were also referred to as exochelins, Sect. 2.5 (128)) from
Mycobacterium spp. For reviews see (85, 331, 369). They have the same basic
skeleton as the nocobactins, but the 4,5-double bond of the oxazole ring is saturated.
A series of differently substituted representatives has been isolated (see Table 5).
The major group comprises mixtures carrying saturated and unsaturated long-chain
fatty acid residues as substituents of the hydroxamic acid unit formed by the
N6-amino group of lysine. For some (“J”, M, and N), the fatty acid residues are
located in the chain, as for the nocobactins. Representatives of the MAIS group
(Mycobacterium avium, M. intracellulare, M. scrofulaceum) possess two long

Table 4. The nocobactin family

HO COR3
N
(CH2)4
OH
N CO-NH-CH-CO-O-CHR2-CR1-CO-NH
CH3 N
O
O CH3 OH
R4

Compound R1 R2 R3 R4 References
nocobactin NA H C9H19,C11H23 CH3 H (294, 295)
formobactin CH3 C9H19 H H (252)
amamistatin A CH3 C7H15 H H (191, 341)
amamistatin B CH3 C7H15 H OCH3 (191, 341)
Microbial Siderophores 21

Table 5. The mycobactin family (adapted from (369))

HO COR3
N
(CH2)4
OH
N CO-NH-CH-CO-O-CHR2-CHR1-CO-NH

N
O
O R4 OH
R5

Mycobactin R1 R2 R3 R4 R5 References
A H CH3 C13 H CH3 (332)
F H CH3 C9-17 CH3 H (332)
H H CH3 C17,19 CH3 CH3 (381)
J CH3 CH(CH3)2 C15 H H (224)
“J” CH3 b a CH3 H (18)
P CH3 C2H5 C13-19 H CH3 (329)
R CH3 C2H5 C19 H H (332)
S H CH3 C13-19 H H (381)
T H CH3 C14-21 H H (330)
M CH3 C14-17 CH3 CH3 H (332)
N CH3 C14-17 C2H5 CH3 H (332)
MAIS CH3 b a H H (18)
CH3 b a CH3 H (18)
carboxy H CH3 c H H (128)
H CH3 c CH3 H (128)
CH3 C2H5 d CH3 H (199, 292)
a – unsaturated alkyl chain, b – saturated alkyl chain, c – saturated and unsaturated dicarboxylic
acid methyl ester, d – unsaturated dicarboxylic acid

chain fatty acid residues. The stereochemistry of most chiral centers has been
determined. For the Fe3+ complex of mycobactin P an X-ray analysis is available
(157). For the carboxymycobactins the residues R3 in Table 5 are saturated or
unsaturated alkyl groups with terminal carboxyl groups or their methyl esters.
Transvalencin Z (245a) from Nocardia transvalensis could be a precursor or
side product of mycobactin biosynthesis, possibly acquired from a vagabonding
gene. It comprises the left part of the serine/salicylic acid based molecules (Table 5
R4 = R5 = H) and ends with N6-formyl-Lys (R3 = H, no N-hydroxy group). The
stereochemistry of the two chiral centers was not determined. Transvalencin Z
seems not to bind Fe3+.
Iron uptake of Mycobacterium smegmatis involving mycobactin S was studied
with 55Fe3+ (293). Mycobactin is not given off into the surrounding medium but is
located instead in the lipid envelope of the cell and is active in the trans-membrane
transport of Fe3+ (taxi mechanism). Iron is relased at the inside of the membrane by
a reductive mechanism. There is some evidence that salicylic acid is the extracel-
lular siderophore.
Corrugatin (34) (Fig. 9) is the siderophore of Pseudomonas corrugata (302). It
was also found as secondary siderophore of several pyoverdin producing Pseudo-
monas strains as P. fluorescens, occasionally in slightly modified forms such as
22 H. Budzikiewicz

HN HN
C7H15CONH CO-NH-CH-CONH-CH-CONH-CH-CONH-CH CONH-CH-COOH
N N
CHOH (CH2)n CH2OH CH2OH CHOH CHOH
NH2 COOH COOH
N
HN
L-OHHis L-Dab L -Dab L-Ser D-Ser L-OHAsp L-Dab L-OHAsp
D-Orn

Fig. 9. Corrugatin (n = 2, L-Dab) (34) and ornicorrugatin (n = 3, D-Orn) (35)

36: RCO-OHAsp-Dab-Ser-acetylOHOrn-Ser-acetylOHOrn
37: RCO-OHAsp-Ser-Ser-Gln-acetylOHOrn-Ser-acetylOHOrn
38: RCO- acetylOHOrn-acetylOHOrn-Ser-acetylOHOrn (2 D-,1L-Orn, L-Ser)
39: RCO-OHAsp-Ser-Gln-Ser-acetylOHOrn-Dhb-Ser-cOHOrn

a H b
O N HOOC OH
H O
HO Ser CH N
RCONH Ser
NH O N
RCO-NH
O

Fig. 10. Amphiphilic marine siderophores

ornicorrugatin (35) where one Dab is replaced by Orn (218), or with OHHis instead
of OHAsp as the C-terminus (S. Matthijs, unpublished).
A group of amphiphilic siderophores was isolated from marine bacteria (410),
the marinobactins (Fig. 10, 36), from Marinobacter sp., aquachelins (Fig. 10, 37),
from Halomonas aquamarina (215, 217), the amphibactins (Fig. 10, 38), from
Vibrio sp. (216), and the loihichelins (Fig. 10, 39), from Halomonas sp. (150).
They all comprise series of related molecules differing in the nature of the saturated
or unsaturated fatty acid (for amphibactins and loihichelins also 3-hydroxy
fatty acids) linked to the N-terminus (see also ochrobactins and synechobactins,
Sect. 4.1). Structure elucidations were effected by spectroscopic methods and
degradation studies. For the marinobactins a N-terminal nine-membered lactam
ring was suggested to be formed by an amide bond between the carboxyl group of
Asp and the C-4 amino group of Dab (Fig. 10, a). It may be suggested that rather a
condensation with the amide carbonyl group had occurred (Fig. 10, b; cf. Chart 1).
This would keep the a-hydroxycarboxyl grouping of OHAsp intact, which acts as a
binding site for Fe3+ and is essential for photolytic degradation. The rather scarce
structural data presented do not allow a decision to be made. The siderophores show
a strong affinity to lipid membranes (389). The Fe3+ complexes of aquachelins and
marinobactins suffer degradation under sunlight irradiation. For the Fe3+-aquachelin
complexes the formation of Fe2+, of hydrophobic and of hydrophylic cleavage
Microbial Siderophores 23

Fe3+
O–
- CO
O
H O H O
RCO N Fe2+ + H N
N
H O RCO O
OH OH

Chart 2. Light-induced degradation of Fe3+-aquachelins

products was observed. For the latter a N-formyl-Ser terminus was suggested based
on mass spectral data (Chart 2) (12). There is evidence that this type of photolytic
degradation is common for siderophores containing a-hydroxycarboxyl ligands
(13, 150, 401).

2.9. Pseudomonas mendocina Siderophores

From Pseudomonas mendocina five siderophores were isolated by chromatography.

They are reported to have identical molecular masses of 1,152 Da (the also reported
(3a) value of 929 Da is an error; L. E. Hersman, private communication) and an
identical amino acid composition, which has not been revealed (141a). Color
reactions show the presence of a hydroxamate, but not of a catecholate grouping.
A gene analysis suggests a partial sequence acyl-Asp-Dab-Ser-formylOHOrn-Ser-
formylOHOrn where asparagine could be OHAsp and the C-terminal ornithine
cOHOrn (9b). In which way the five isomeric siderophores with identical molecular
masses differ from each other is not clear.

3. Siderophores Based on Diamino- and Triaminoalkane

Skeletons

3.1. Rhizobactin

Rhizobactin (40) is the siderophore of Rhizobium meliloti (328). It contains one

a-hydroxycarboxylic acid and two a-amino acid units as probable binding sites for
Fe3+. Acid hydrolysis yields inter alia L-malic acid. The stereochemistry of the
other two chiral centers is not known.
40 HOOC-CH(CH3 )-NH-(CH2 )2 -NH-CH(COOH)-(CH2 )4
-NH-CO-CH2 -CHOH-COOH
24 H. Budzikiewicz

3.2. Catecholate Siderophores

For other catecholate siderophores, see the peptide-based siderophores above

(Sect. 2.7) and the citric acid derivatives below (Sect. 4.3); for a review on
syntheses, see (24), for a general review, (38).
The tricatecholate siderophore protochelin (41) (Fig. 11) was obtained from a
methanol – bacterium (351). Subsequently it was also found to be produced by
Azotobacter vinelandii (72, 360) together with its constituents 2,3-dihydroxyben-
zoic acid, azotochelin (bis-DHB lysine) (70) and aminochelin (mono-DHB cadav-
erine) (273). Cepaciachelin from Burkholderia cepacia (15) lacks the DHB
residue from the aminochelin part of protochelin. The amino acid in all com-
pounds is L-lysine. Azotobacter vinelandii shows an interesting rationale when
confronted with a deficiency in iron supply. At concentrations >7 mM, 2,3-
dihydroxybenzoic acid is secreted, between 3 and 7 mM, the di- and tricatecholate
siderophores are produced, and at still lower concentrations, it is resorted to
azotobactin D (see above Sect. 2.2) (72). Myxochelin A from Angiococcus
disciformis (197) and Nonomuraea pusilla (239a) can be considered as a reduc-
tion product of azotochelin (lysinol instead of Lys). The absolute configuration of
lysinol (S) was determined by synthesis. Both antipodes show about the same
antitumor activity (239a).
Pistillarin was first isolated from Clavariadelphus pistillaris and from several
Ramaria spp. (Basidiomycetes) (334). Recently, it was found to be produced also
by the marine fungus Penicillium bilaii (56). Like siderochrome II below it is a
spermidine derivative substituted only at the terminal NH2-groups (N1, N10-di-(3,4-
dihydroxy)benzoyl-spermidine). Its synthesis and that of siderochrome II was
reported, their siderophore activity and their complexation with Fe3+ (1:1 com-
plexes) was investigated (102, 299). A derivative of pistillarin substituted at all
three amino functions has not been reported yet.
When DHB is bound to serine or threonine cyclization may occur resulting in an
oxazoline ring (cf. above anachelin, Sect. 2.3, and mycobactins, Sect. 2.8). It has
been discussed whether the oxazoline nitrogen atom may act as a ligand site (see
below, (303)). This would explain why DHB is replaced by a salicylic acid residue
in some cases.
To this group of siderophores belong photobactin (42a) from Photorhabdus
luminescens (Fig. 12) (66), derived from 1,4-diaminobutane substituted by DHB
and by cyclized DHB-Thr (1H-NMR data indicate that the substituents of the
oxazoline ring are in trans positions; the absolute stereochemistry is not known),

OH
OH OH
OH
OH NH-CO OH
CO-NH-(CH2)4 -CH-CO-NH-(CH2 )4 NH-CO

Fig. 11. Protochelin (41)

Microbial Siderophores 25

OH

OH
OH

O N OH
NH-(CH2)n -NH-CO
C
O
42a: n = 4
42b: n = 3

Fig. 12. Photobactin (42a), serratiochelin (42b)

OH
OH N O OH

OH CO OH
CO-NH-(CH2)3-N-(CH2)n-NH-CO

43: n = 4, R = OH
44: n = 4, R = H
45: n = 3, R = OH

Fig. 13. Agrobactin (43), parabactin (44), fluvibactin (45)

and its lower homolog serratiochelin (42b) from Serratia marcescens derived
from 1,3-diaminopropane. Its structure including the absolute stereochemistry
(L-Thr) was confirmed by synthesis (101).
Spermidine derivatives are agrobactin from Agrobacterium tumefaciens
(Fig. 13, 43) (268), for which the structure was confirmed by X-ray analysis
(109) and synthesis of the hydrolyzed form (DHB-Thr) agrobactin A (283), and
parabactin (Fig. 13, 44) from Paracoccus denitrificans (284). Two syntheses are
reported for parabactin (28, 28c, 255) (see Sect. 8.3). The open form (parabactin A)
as well as the precursors 2,3-dihydroxybenzoic acid and a compound with a free
central NH group (N1, N10-di-DHB-spermidine, siderochrome II) were also found
(347). The 1:1 Ga3+/Lig complex shows L-cis configuration (28a). Parabactin also
forms a 1:1 complex with Fe3+ (347) for which the structure was investigated by X-
ray photoelectron and electron spin resonance spectroscopy. In particular, the
question as to whether the oxazoline nitrogen acts as a binding site has been
discussed. An experimental proof seemed not to be possible (303).
Iron transport was studied using the 55Fe3+- and 3H-complexes of parabactin
(25). After a quick uptake of 10% of both labels there was a continuing steady
uptake of 55Fe3+ while the amount of 3H remained constant. This could either mean
that after binding to the cell surface 55Fe3+ only is transferred into the cell (“taxi
mechanism”) or there is a fast re-export of the ligand. A decision in favor of the
26 H. Budzikiewicz

R
R

OH
HO
N O OH
O N

CO OH
CO-NH-(CH 2 ) 3 -N-(CH 2)3 -NH-CO

46: R = OH
47: R = H

Fig. 14. Vibriobactin (46), vulnibactin (47)

taxi-mechanism could be reached by offering the Ga3+ complex of [3H]-parabactin

(Ga3+ cannot be released reductively in the cell and hence a re-export of the ligand
is not possible). The uptake curve resembled that of ferri-[3H]-parabactin: a small
amount of complex is bound to the cell surface, but there is no transport of the
ligand in the cell. This is in agreement with temperature studies (30 and 4 C). While
the uptake of 55Fe3+ decreases that of 3H is not influenced.
Fluvibactin (Fig. 13, 45) from Vibrio fluvialis (391) differs from agrobactin by
replacement of spermidine by norspermidine. Also here the precursor with a free
central NH group could be isolated. Vibriobactin from Vibrio cholerae (Fig. 14, 46)
contains two cyclized DHB-Thr substituents (129). Syntheses of agrobactin, fluvi-
bactin and vibriobactin are published (26, 30, 308). In vulnibactin from Vibrio
vulnificus (Fig. 14, 47) (264) two DHB groups are replaced by salicylic acid units.
The precursor with a free central NH group was also found.

3.3. Hydroxamic Acid Siderophores

Bisucaberin (48) from Alteromonas haloplanktis (181) is a cyclic dimer of succinyl-

(N-hydroxycadaverin) (348); cf. the cyclic trimer proferrioxamine E (Table 6).

48 ½-CO-CH2 -CH2 -CO-NH-CH2 -CH2 -CH2 -CH2 -CH2 -NOH-2

In putrebactin from Shewanella putrefaciens (201) cadaverine is replaced by

putrescine (49, R = H). For the cyclic trimer, see proferrioxamine X2 in Table 6.
The arctic S. gelidimarina living in a habitat with extremely low iron supply
produces a cell-associated hydroxamic acid siderophore with the mass 977 Da for
[M+H]+ of unknown structure (274).
Alcaligin from Alcaligenes denitrificans (260) and from Bordetella spp. (244) is
a cyclic dimer of succinyl-N1,3S-dihydroxyputrescine (49, R = H) confirmed by
synthesis (402).
49 ½-CO-CH2 -CH2 -CO-NH-CH2 -CHR-CH2 -CH2 -NOH-2
Microbial Siderophores 27

Table 6. Structures and nomenclature of proferrioxamines (pFO) (adapted from (110))a

H2 N-ðCH2 Þm -NOH-CO-CH2 -CH2 -CO-NH-ðCH2 Þn -NOH-CO-CH2 -

CH2 -CO-NH-ðCH2 Þo -NOH-CO-CH2 -CH2 -CO-NH-ðCH2 Þp -
NOH-CO-CH2 -CH2 -COOH

pFO cyclic m n o p N-terminus C-terminus Abbreviation References

A1
5 5 4 0
Ac pFO554Ac (185a)
A2
5 4 4 0
Ac pFO544Ac (185a)
B
5 5 5 0
Ac pFO555Ac (30e)
D1
5 5 5 0 Ac Ac Ac-pFO555Ac (185b)
D2 þ 4 5 5 0
Suc pFO455c (185a)
Eb þ 5 5 5 0
Suc pFO555c (155a, 186)
G1c
5 5 5 0
Suc pFO555 (186a)
G2a
5 5 4 0
Suc pFO554 (115)
G2bc
5 4 5 0
Suc pFO545 (115)
G2cc
4 5 5 0
Suc pFO455 (115)
H
5 5 0 0 Suc Ac Suc-pFO55Ac (1)
T1 þ 5 5 5 5
Suc pFO5555c (115)
T2 þ 4 5 5 5
Suc pFO4555c (115)
T3 þ 3 5 5 5
Suc pFO3555c (115)
X1 þ 4 4 5 0
Suc pFO445c (115)
X2 þ 4 4 4 0
Suc pFO444c (115, 398)
X7 þ 3 5 5 0
Suc pFO355c (115, 398)
a
Structures were not established for C and F (Rf values and physical constants) (30d), T4-T6, and
X8, X9 (mass spectra) (115)
b
Identical with norcardamin (186, 338)
c
Accompanied by “truncated” compounds without the terminal succinic acid unit (G1t, G2bt, G2ct)
(115, 398)

Alcaligin forms at pH 2.0 a 1:1 and at pH 6.0 a 2:3 Fe-to-ligand complex. The
structure (Plate 3) of the (Fe3+)2Lig3 complex was studied by X-ray analysis (156).
One ligand bridges two metal ions while the remaining two are coordinated with a
single Fe3+ each. The metal centers show L-configuration.
Alcaligin E from Alcaligenes eutrophus is described from color tests as a
phenolic siderophore (126a). According to a recent publication (90a) it is identical
with staphyloferrin B, a citrate siderophore (Sect. 4.2). No further information is
given to resolve these discrepancies.
A group of related siderophores comprises the desferri- or deferriferrioxamines
(occasionally abbreviated as desferrioxamines) or proferrioxamines. Originally
they were obtained from Actinomycetes, mainly Nocardia and Streptomyces spp.
(187) and later found to be produced also by Erwinia spp. (several representatives)
(e.g. (30a, 113, 115, 180)), Arthrobacter simplex (B), Chromobacterium violaceum
(E) (246a), and by Pseudomonas stutzeri (several) (229a, 246, 398). They consist of
three (or in rare cases four) mono-N-hydroxy-1,4-diaminobutane (putrescine),
mono-N-hydroxy-1,5-diaminopentane (cadaverine) or (rarely) mono-N-hydroxy-
1,3-diaminopropane units connected by succinic acid links. The hydroxylated
terminus carries an acetyl or a succinyl (as in the structural formula heading Table 6)
28 H. Budzikiewicz

Plate 3. X-ray structure of ferri-alcaligin (ferri-49)

residue, and in the latter case the free carboxyl group and the free N-terminus may
form a macrolactam. The terminal acid residue can also be missing (referred to as
“truncated”) (115, 398). By feeding of suitable diamino precursors to the culture
medium unnatural analogs can be obtained (111, 194, 227). At pH values above 6.5
(Fe3+)2Lig3 complexes prevail, in more acidic media Fe3+Lig is formed (194). The
crystals of the Fe3+Lig complexes of ferrioxamine D1 and E are racemic mixtures of
L-cis and D-cis coordination isomers (154, 366a). The outer membrane receptor
protein of Erwinia amylovora was structurally determined (180). Siderophore
activity was demonstrated for 55Fe-labeled ferrioxamine E (30a). For the mass
spectrometric analysis, see (112a).
Microbial Siderophores 29

Originally the various natural representatives had been designated by capital

letters, but later a nomenclature system was proposed (110). In short, the indices
and modifications as listed in Table 6 (p = 0 means that the entire fourth diami-
noalkane-succinyl unit is missing) are grouped around the acronym pFO. The
system is essentially self-explanatory; for details and possible extensions see the
original publication.

4. Citrate Siderophores

For a review, see (39). Some citrate siderophores are accompanied by cyclic imide
structures formed by the loss of water from the central carboxyl group and a lateral
amide NH (Chart 3). They are usually designated by an A following the name of the
siderophore. Free citric acid can be a true siderophore, e.g. for Bradyrhizobium spp.
(205), Pseudomonas aeruginosa (213), and Mycobacterium smegmatis (228a).
The mode of the uptake differs. Bradyrhizobium and Pseudomonas incorporate
ferric citrate but Pseudomonas shows also a citrate mediated Fe2+ uptake, while in
the case of Mycobacterium no citrate enters the cell. Ferric citrate is a complex
system depending on the pH of the solution and the relative concentration of the two
constituents (333a, 333b). In an acidic milieu equimolar concentrations form
[FeCit]-, at about pH 4 polymerization starts resulting at pH 8–9 in an insoluble
complex with an iron hydroxide core and citrate ions bound to the surface. With a
citrate excess species like [FeCit2]5- are discussed.
It should be mentioned that the central carbon atom of citric acid becomes chiral
when the two peripheral carboxy groups are substituted differently (examples will
be found below). For enzyme reactions it is a prochirality center. This has been
shown for vibrioferrin (58) and staphyloferrin B (59).

4.1. Siderophores with Two Hydroxamic Acid Units

In siderophores of this series, 1,3-diaminopropane, 1,5-diaminopentane, or lysine

(by its a-amino group) is connected to the outer two carboxyl groups of citric acid.

CO-NHR CO-NHR
OH OH
– H2O
+ H2O
COOH CO
CO-NHR OC NR

Chart 3. Cyclization of citrate siderophores to amidic structures

30 H. Budzikiewicz

These spacers, in turn, are acylated and derivatized by a N-hydroxy group thus
forming hydroxamic acids. For a synthesis concept see (404).
Schizokinen (Fig. 15, 50) was first isolated from Bacillus megaterium (53), sub-
sequently from Ralstonia solanacearum (43), Rhizobium leguminosarum (339), and
several species of the cyanobacterium Anabena (e.g. (326)). It was named after its
cell division promoting effect observed with Bacillus cultures (200). Its structure
was elucidated by degradation and spectral data and confirmed by synthesis (43,
202, 237, 248). For a compilation of details on structural data the review (39)
should be consulted. Both natural and synthetic schizokinen is accompanied by the
cyclized schizokinen A (43, 202, 237, 248). Schizokinen forms a 1:1 complex with
Fe3+, but at the central hydroxy group acetylated schizokinen yields (Fe3+)2Lig3.
This proves that the central unit is one of the binding sites (285). Also N-deoxy-
schizokinen from Bacillus megaterium lacking one hydroxamic acid unit still binds
Fe3+ (158). Whether it acts as a siderophore is not known.
The schizokinen-mediated Fe3+ transport in Bacillus megaterium was studied by
double labelling with 59Fe and 3H (8). At 37 C, uptake of 59Fe and of 3H are parallel
during the first 30 sec, then that of 59Fe continues until it levels off after 2 min,
while that of [3H]-schizokinen drops to a low constant level. At 0 C, uptake of both
labels reaches this low level which is obviously due to the binding of the ferri-
siderophore to the cell surface. At 37 C, transport into the cell, release of iron, and
re-export of the ligand follow. Apparently a shuttle mechanism takes place, cf. the
experimental results obtained with parabactin (Sect. 3.2) indicative of a taxi
mechanism.
Arthrobactin (Fig. 15, 51) was obtained from Arthrobacter spp. and originally
described as the growth factor of A. terregens, the “terregens factor” (51). Its
structure was elucidated (207) and confirmed by synthesis (202). Also the structure

CO-NH-CHR1 -(CH2)n -NOH-CO-R2

OH

COOH

CO-NH-CHR1 -(CH2)n -NOH-CO-R3

50: R1 = H, R2 = R3= CH3, n = 2

51: R1 = H, R2 = R3 = CH3 , n = 4
52: R1 = H, R2 = R3 = (E)-CH=CH-(CH2 )4 -CH3 , n = 2
53: R1 = COOH, R2 = R3 = CH3, n = 4
54: R1 = COOH, R2 = R3 = (E)-CH=CH-C6H5 , n = 4
55: R1 = COOH, R2 and R3 alkyl or alkenyl groups, n = 4
56: R1 = H, R2 = CH3 , R3 = (E)-CH=CH-(CH2)6-CH3 , n = 2
57: R1 = H, R2 = CH3 , R3 = alkyl groups, n = 2

Fig. 15. Citrate siderophores with two hydroxamic acid units

Microbial Siderophores 31

of acinetoferrin from Acinetobacter haemolyticus was established (Fig. 16, 52)

(265) and confirmed by synthesis (375). It shows strong interaction with lipid
membranes like the marine liposiderophores above (211) (Sect. 2.8).
Aerobactin (Fig. 15, 53) was first isolated from Aerobacter (Enterobacter)
aerogenes (126), Enterobacter cloacae (368) and subsequently from various enter-
obacteria such as Escherichia (376), Salmonella (225), Shigella (277), Yersinia
(340), but also from Erwinia carotovora (163), Pseudomonas sp. (52) and Vibrio
spp. (141, 266). Aerobactin is an important virulence factor for enterobacteria (75).
Aerobactin contains L-lysine. A synthesis is described (222). The bright orange Fe3+
complex was investigated in detail (predominant L configuration in solution,
stability constant, redox potential) (138). Fe3+ transport was studied by double
labelling (59Fe and 3H) (8). The results corresponded to those obtained with
schizokinen. Aerobactin binds to the same receptor as the bacteriocin cloacin
DF13 and thus alleviates the growth inhibiting effect of the latter (368).
Nannochelin C (Fig. 15, 54) from the myxobacterium Nannocystis exedens
contains two L-Lys and two (E)-cinnamic acid units. The reported mono- and
di-methyl esters (nannochelin B and A) may be artifacts from the work-up (198).
A synthesis is described (29) (see Sect. 8.4). The ochrobactins (Fig. 15, 55) isolated
from the sea-shore bacterium Ochrobactrum sp. (214) with the spacer L-lysine are
membrane active due to the fatty acid residues (saturated C8 and (2E)-unsaturated
C8 and C10); cf. lipopeptidic siderophores in Sect. 2.8.
Rhizobactin 1021 (Fig. 15, 56) (for rhizobactin, see diaminoalkane-based side-
rophores, Sect. 3.1) from Rhizobium meliloti (281), contains an acetyl and an
(E)-decenoyl group. Its Fe3+ complex in aqueous solution is L-configured and
forms an equilibrium between a monomeric and a dimeric form that can be
separated by chromatography. A synthesis is described (404).
Synechobactins (Fig. 15, 57) from the cyanobacterium Synechococcus (165),
contain an acetyl and C12-, C10-, and C8-saturated acid residues and thus belong
to the amphiphilic marine siderophores (cf. Sect. 2.8). Both rhizobactin 1021 and
the synechobactins are substituted unsymmetrically. Hence, for each, the central
C-atom of citric acid is chiral, but its stereochemistry has not been determined.
Awaitins are synthetic homologs of siderophores (A: 53, n ¼ 3; B: 50, n ¼ 3; C:
53, n ¼ 2) “awaited” to be found in nature, so far without success (405).

COOH
OH

O
COOH

CO-O-CH2-CH2-NH-CO-CH-N
HO
COOH

Fig. 16. Vibrioferrin (cyclic form) (58)

32 H. Budzikiewicz

4.2. Siderophores with 2-Oxoglutaric Acid Units

N-Alkylated 2-oxoglutaric acid derivatives cyclize at neutral pH values to two

epimeric 5-carboxy-5-hydroxy-2-oxopyrolidine structures (Chart 4). In this way, a-
hydroxycarboxylic acid groupings are formed that can act as ligand sites for Fe3+.
Vibrioferrin (58, Fig. 16) was isolated from Vibrio parahaemolyticus. The
stereochemistry of the central citric acid C-atom is R, that of the alanine part is S
as shown by stereospecific synthesis (411). Iron uptake was studied with 55Fe3+
proving that vibrioferrin acts as a siderophore despite the fact that it has only five
ligand sites, the two a-hydroxy acids and the free citric acid carboxyl group.
Possibly a solvent molecule satisfies the eighth octahedral position (393, 411).
Vibrioferrin is also formed by Marinobacter spp. It is a week Fe3+ chelator
(complexing constant 1024). Its Fe3+ complex is very susceptible to photodegrada-
tion by oxidative decarboxylation of the cyclized 2-oxoglutaric acid unit yielding a
succinimide ring. This species cannot bind Fe3+. The concomitantly formed Fe2+
(cf. Chart 2) is reoxidized to fairly soluble Fe3+ hydroxo complexes, which are
readily taken up by the bacteria (410).
Staphyloferrin B (59, Fig. 17) is produced together with staphyloferrin A (see
below Sect. 4.4) by Staphylococcus hyicus and other staphylococci (94, 131),
by Ralstonia eutropha (250) (¼ Cupriavidus metallidurans (90a)). Comparison
of its CD spectrum with those of model compounds suggests the (S)-configuration
of the central citric acid C-atom. Mass spectral investigations show a 1:1 Fe3+-
to-ligand ratio, and NMR studies of the Ga3+ complex confirm the participation of
the two a-hydroxy- and of the a-amino acid functions in complex formation.
Uptake studies with 55Fe3+ showed that staphyloferrin B acts as a siderophore,
but it is less efficient than staphyloferrin A.

O
O
COOH R-N
R-NH
O HO
COOH

Chart 4. Cyclization of 2-oxoglutaric acid substituents

CO-NH-CH2-CH(NH2)COOH
OH

O
COOH

CO-NH-CH2-CH2-N
HO
COOH

Fig. 17. Staphyloferrin B (cyclic form) (59)

Microbial Siderophores 33

Achromobactin (60, Fig. 18) is produced by Erwinia chrysanthemi in addition to

chrysobactin (see above under the catecholate siderophores, Sect. 2.7). It has two
chiral centers, a L-Dab unit and the central citric acid C-atom (not determined)
(249). Recently, achromobactin was also found to be produced by Pseudomonas
syringae (30b), a very versatile bacterial species (see pyoverdin, Sect. 2.1, and
yersiniabactin, Sect. 5).

4.3. Siderophores with Two Catecholate Units

In petrobactin, spermidine residues are bound to citric acid substituted with 3,4-
dihydroxybenzoyl (27), and not 2,3-dihydroxybenzoyl units (Fig. 19, 61), as
assumed originally (14). One or both of the substituents can carry a sulfonic acid
group in the 2-position of the aromatic ring (Fig. 19, 62 and 63) (142, 149); cf. also
(40). Petrobactin was originally obtained from Marinobacter hydrocarbonoclasticus
(14) and subsequently from Bacillus anthracis (195, 382), B. cereus and B. thu-
ringiensis (195a), its sulfonated derivatives from Marinobacter spp. It is probably
identical with the incompletely characterized anthrachelin (123).
O

CO-O-CH2-CH2-N
OH HO
COOH
O
COOH COOH
CO-NH-CH2-CH2-CH-N
HO
COOH

Fig. 18. Achromobactin (cyclic form) (60)

R1 OH

CO-NH-(CH2)4-NH-(CH2)3-NH-CO- OH
OH

COOH R2 OH

CO-NH-(CH2)4-NH-(CH2)3-NH-CO- OH

61: R1 = R2 = H
62: R1= H, R2 = SO3H
63: R1 = R2 = SO3H

Fig. 19. Petrobactin (61), petrobactin monosulfonic acid (62), petrobactin disulfonic acid (63)
34 H. Budzikiewicz

CO-NH-CHR-(CH2)3-NH-OC
OH HO

COOH HOOC
COOH HOOC

64: R = H
65: R = COOH

Fig. 20. Rhizoferrin (64), staphyloferrin A (65)

4.4. Siderophores with Two Citric Acid Units

(S,S)-(enantio)-Rhizoferrin (Fig. 20, 64) was obtained from Ralstonia pickettii

(251). It is the optical antipode of the fungal (R,R)-rhizoferrin first isolated from
Rhizopus microsporus (93) and subsequently found to be a common siderophore of
Zygomycetes (358). It is accompanied by two dehydration products, which are due
to the formation of one or two imide rings (cf. Chart 3). UV spectral studies
revealed that rhizoferrin forms a 1:1 Fe3+-to-ligand complex despite the fact that
it has only two a-hydroxy acid binding sites (95). NMR studies of the Ga3+ complex
proved the twofold symmetry of the complex and showed that only the carboxyl
groups, but not the hydroxy groups are deprotonated between pH 5.5 and 9.0. The
Fe3+ complex is chiral and shows L-configuration (58). Uptake studies suggest a
shuttle mechanism (61). While Ralstonia accepts both antipodes with equal rates
Rhizopus shows a clear preference for its native (R,R)-enantiomer (251).
Staphyloferrin A (Fig. 20, 65) is a second siderophore of Staphylococcus spp.
(226). D-Ornithine connects the two citric acid parts. Due to the unsymmetrical link
the central C-atoms of the citric acid units are chiral, but their stereochemistry has
not been determined. Another consequence of the asymmetric structure is that two
mono- and one di-dehydration products are observed. Staphyloferrin A forms a 1:1
Fe3+-to-ligand complex, which is preferentially L-configured. For steric considera-
tions only cis-(SR0 ) or cis-(RS0 ) arrangements can be considered. Uptake experi-
ments with 55Fe showed that it is a true siderophore (193).

4.5. Legiobactin

Legionella pneumophila produces a siderophore named legiobactin, which shows

no catecholate or hydroxamate reactions (206). Enzymatic studies suggest a citrate
structure in agreement with the data obtained by mass spectrometry (molecular
mass ca. 350 Da) and NMR (three carbonyl and ten aliphatic C atoms). It is not
clear yet as to whether legiobactin is essential for the iron acquisition in the aqueous
habitat of the bacterium or during lung infection (2, 65).
Microbial Siderophores 35

5. Pyochelin and Related Structures

This group comprises condensation products of salicylic acid with cysteine giving a
thiazoline ring. For a review, see (310). Some structurally related compounds will also
be mentioned here. Salicylic acid isolated from Burkholderia (Pseudomonas) cepacia
was named azurochelin (333). It was found to act as a siderophore, e.g. for Pseudo-
monas fluorescens (230) and P. syringae (178); see also Mycobacterium smegmatis
(Sect. 2.8). For details on the siderophore activity of salicylic acid, see (359).
The structure of pyochelin (for a detailed bibliography, see (37)), a secondary
siderophore of Pseudomonas aeruginosa and of Burkholderia cepacia was estab-
lished (73) as 2-(2-o-hydroxyphenyl-2-thiazolin-4-yl)-3-methylthiazolidine-4-
carboxylic acid. It consists of a mixture of two easily interconvertible stereoisomers
(pyochelin I and II) differing in the configuration of C-200 . They can be separated
by chromatography, but in methanolic solution (not in DMSO) the equilibrium
(ca. 3:1) is restored quickly. For a discussion of the mechanism of isomerization,
see (37, 317).
The relative and absolute stereochemistry (40 R,200 R,400 R) of pyochelin I (Fig. 21,
66) were established by an X-ray analysis of its Fe3+ complex (316). Fe3+ is
associated with the phenolate and the carboxylate oxygen ions and with the two
nitrogen atoms. Two of these units are bridged by an acetate ion and a water
molecule satisfying the remaining two ligand loci of Fe3+ (Plate 4). However, by
titration a (Fe3+)/pyochelin ratio of 1:2 has been determined at pH 2.5 (370). This
may be due to a partial protonation of the complexing sites. From Burkholderia
cepacia, a mixed complex was obtained comprising Fe3+/pyochelin/cepabactin
1:1:1 (see Sect. 6 below) (188). An X-ray analysis has been performed of ferri-
pyochelin bound to its outer membrane receptor (67a). Pyochelin II has the
configuration (40 R,200 S,400 R). It does not complex Fe3+ (140).
Several syntheses resulting in mixtures of stereoisomers (C-40 and C-200 ) have
been developed (6, 301, 397) (Sect. 8.5). Pseudomonas fluorescens CHA0 produces
enantio-pyochelin (394). The two optical antipodes are not accepted reciprocally by
the two Pseudomonas species.
Pyochelin is a non-ribosomal condensation product of salicylic acid with two
molecules of cysteine (289). Intermediates with one cysteine unit are aeruginoic
acid (Fig. 21, 67) first isolated from Pseudomonas aeruginosa (390), and (+)-(S)-
4,5-dihydroaeruginoic acid, from Pseudomonas fluorescens (57). Detailed studies
(274a) suggest that N-hydroxybenzoyl-L-cysteine bound to the synthetase

OH OH

H COOH
N N N
4' 2'' 4'' COOH
S S
H S
66 67

Fig. 21. Pyochelin I (66), aeruginoic acid (67)

36 H. Budzikiewicz

Plate 4. X-ray structure of ferri-pyochelin I (ferri-66)

OH

N H CHOH-C(CH3)2
N
4' 2'' 4''
C5H11 S N S
H S

HOOC

Fig. 22. Micacocidin (68)

racemizes, that bound dihydroaeruginoic acid is still a racemate, and that in the
further steps only the 40 (R) isomer is used.
Micacocidin (Fig. 22, 68) from Pseudomonas sp. complexes Fe3+ and other
metal ions (189, 190). Whether it acts as a siderophore has not been investigated.
A stereospecific synthesis was elaborated (161, 161a), but the same isomerization
problems at C-40 and C-200 were encountered as had been observed with pyochelin
(see Note 14 in (161)).
Yersiniabactin (Fig. 23, 69) was obtained from Yersinia spp., and is produced
also by Pseudomonas syringae (49) and Escherichia coli (178). Its structure was
elucidated independently by two groups and given the names yersiniabactin (96)
Microbial Siderophores 37

OH COOH
OH N
H C
N H C
N S
H
S
H S

Fig. 23. Yersiniabactin (69)

Plate 5. X-ray structure of ferri-yersiniabactin (ferri-69)

and yersiniophore (64). The configurations of the four chiral centers were not
determined, but epimerization probably at C-10 (corresponding to C-200 of pyoche-
lin) was indicated. A recent X-ray analysis (Plate 5) of the Fe3+ complex (238)
established the absolute stereochemistry [N-2 (R), C-9 (R), C-10 (R) as for pyoche-
lin, C-12 (R), C-13 (S), C-19 (S)], with D-configuration.
Anguibactin (Fig. 24, 70) from Vibrio anguillarum (171) contains DHB
condensed with Cys (stereochemistry not determined). It is accompanied by a
biosynthetic by-product (311) without the histamine part as its methyl ester.

6. Miscellaneous Siderophores

Desferri-ferrithiocin from Streptomyces antibioticus (Fig. 25, 71) (4, 254) is struc-
turally related to the pyochelin group. It is (S)-configured and forms a Fe3+Lig2
complex (131a).
Cepabactin (Fig. 25, 72) from Burkholderia cepacia (232) forms a (Fe3+)Lig3
complex (386) and a mixed Fe3+ complex with pyochelin (Sect. 5).
38 H. Budzikiewicz

R'
OH
NH
O
N
N N
X OH
R
70: X = S, R = H, R' = OH
78: X = O, R = CH3, R' = OH
79: X = O, R = CH3, R' = H

Fig. 24. Anguibactin (70), pre-acinetobactin (78), pre-pseudomonine (79)

OH

N
N COOH CH3O N O
S OH
71 72

Fig. 25. Desferri-ferrithiocin (71), cepabactin (72)

OCH3

HSCO N COSH N R
OH
73 74: R = COSH
75: R = COOH

Fig. 26. Pyridine-di(monothiocarboxylic acid) (73), thioquinaldic (74), quinaldic acid (75)

Pyridine-2,6-di(monothiocarboxylic acid) (Fig. 26, 73) [for a review, see (36),

cf. also (37)] was obtained from Pseudomonas putida (262) and later from
Pseudomonas stutzeri (203). It forms a brown Fe3+ complex and a blue Fe2+
complex (both FeLig2) (143), which may be accompanied by complexes carrying
two additional cyanide ions (145). An X-ray analysis (Plate 6) of the Fe3+
complex of 73 shows a distorted octahedral symmetry (143). There is evidence
that a sulfenic acid residue (-CO-SOH) is the biosynthetic link between -COOH
and -COSH (144).
From iron-deficient cultures of Pseudomonas fluorescens, 8-hydroxy-4-methoxy-
monothioquinaldic acid (thioquinolobactin) together with the corresponding
quinaldic acid (quinolobactin) (Fig. 26, 74 and 75), could be isolated (258).
Quinolobactin can act as an alternative siderophore of Pseudomonas fluorescens
(245), although it is the hydrolysis product of the thioacid (220). Its synthesis and
complex formation as (Fe3+)Lig2 was described (98).
Pseudomonine (Fig. 27, 76) is produced by Pseudomonas fluorescens strains (7,
228) and by P. entomophila, where it can act as a secondary siderophore (209). The
substituents on C-4 and C-5 of the isoxazolinone ring are in trans positions (311).
The complex formation has not been studied. In vitro enzyme-catalyzed synthesis
studies (311, 388) showed that initially the intermediate pre-pseudomonine (Fig. 24,
79) is formed, which non-enzymatically rearranges to pseudomonine.
Microbial Siderophores 39

Plate 6. X-ray structure of the Fe3+-complex of 73

HO 5 O
CO-NH 4
N NH
O
N
76: R = H
77: R = OH

Fig. 27. Pseudomonine (76), acinetobactin (77)

An analogous set of studies demonstrated that acinetobactin from Acinetobacter

baumannii (392) has actually the structure 77 shown in Fig. 27 and that the one
originally proposed (Fig. 24, 78) is that of pre-acinetobactin. In contrast, the
thiazoline ring of anguibactin (Fig. 24, 70) (see above Sect. 5) is stable. Acineto-
bactin forms a 1:1 complex with Fe3+.
Domoic acid (Fig. 28, 80) (263) is a neuro-phycotoxin responsible for the mortality
of wildlife and for amnesic shellfish poisoning (ASP) of humans during algal bloom.
Domoic acid was first isolated from the red alga Chondria armata (“domoi” in
Japanese), and it is produced also by diatoms, such as Pseudo-nitzschia spp. For the
latter, evidence has been presented that it is involved in iron acquisition (307).
40 H. Budzikiewicz

COOH
HOOC

N COOH
H

Fig. 28. Domoic acid (80)

H2O NH2

N COOH N COOH
N
O

Chart 5. Proferrorosamin A (81)

OH
R OH
N
N
CONH2

Fig. 29. Siderochelin A (R = CH3) (82), B (C-3 epimer) (83) and C (R = C2H5) (84)

The smallest hydroxamate siderophore is N-methyl-N-thioformylhydroxyla-

mine, CH3-N(OH)-CHS, named thioformin (100) or fluopsin (325). The synthesis
was described (CH3-N(OH)-CHO + P2S5 or CH3-N(OH)-H + HCSSK) (100, 166a).
It forms a purple Fe3+Lig3 complex. Pseudomonas mildenbergii produces
N-methyl-N-phenylacetylhydroxylamine (CH3-N(OH)-CO-CH2-C6H5) (159), which
also forms a purple Fe3+ complex.

7. Fe2+ Binding Ligands

Pseudomonas roseus fluorescens (288), Pseudomonas GH (324) and Erwinia

rhapontici (113) produce pro-ferrorosamine A (81), also named pyrimine, which
forms a red (Fe2+)Lig3 complex. Under acidic conditions, an open form of
pro-ferrorosamine A prevails, which cannot bind Fe2+ (Chart 5). Pro-ferrorosamine
B is probably an artifact produced by condensation of pro-ferrorosamine A with
CHO-COOH. Pro-ferrorosamine A is essential for iron uptake by Pseudomonas
(367) and for the pathogenicity of Erwinia (114).
Structurally closely related is the Nocardia metabolite, siderochelin, for which the
structure and relative and absolute stereochemistry were all established by X-ray
crystallography (208, 267). It is a mixture of two epimers A and B (Fig. 29, 82 and
83). Siderochelin C, with an ethyl residue (Fig. 29, 84), was obtained from a different
actinomycete, tentatively identified as Streptoalloteichus sp. (239).
Microbial Siderophores 41

3–
R-OC NO–
Fe2+
O 3

85: R = p-CH2=CH-C6H4-O-
86: 2 R = p-CH2=CH-C6H4-O-, 1 R = p-CHOH=CH-C6H4-O-
87: 2 R = p-CH2=CH-C6H4-O-, 1 R = p-HOOC-CH=CH-C6H4-C-O-
88: R = NH2

Fig. 30. Ferroverdins

The green pigments produced by Streptomyces spp. chelating Fe2+ with

o-nitrosophenolate residues are occasionally referred to as siderophores, but whether
they are really involved in iron metabolism has not been investigated. Ferroverdin A
(11) forms a (Fe2+)Lig3 complex (55), with the ligand being p-vinylphenyl-3-nitroso-
4-hydroxybenzoate (Fig. 30, 85). In ferroverdin B and C, one of the three ligands is
substituted at the vinyl group (Fig. 30, 86 and 87) (346, 361). From Streptomyces
murayamaensis, a precursor of ferroverdin was obtained (Fig. 30, 88) (69).
For a further chelator of Fe2+, see pyridine-2,6-di(monothiocarboxylic acid)
above (Sect. 6).

8. Selected Syntheses

In this section the syntheses of several typical siderophores will be presented in a

summarized form pointing out interesting features.

8.1. Anachelin H (10)

The challenge lay in the stereochemically correct synthesis of the polyketide part of
the molecule. Starting from L-serine (89) (Chart 6) by C2-elongation steps, reduction
of the obtained keto functions including adequate protection and deprotection, and
introduction of the salicylic acid residue the four stereoisomeric 3,5-diols (90) were
obtained. Comparison of the 1H-NMR data with those of anachelin (10) showed that
the isomer with (3R,5S,6S) configuration was the correct starting material.
The chromophore part was prepared from Boc-protected N, N-dimethyl-L-DOPA
(91), reduction to the diamine 92 and tellurium-mediated oxidative ring closure
(93). The free amino group of 94 was coupled with protected L-Ser and L-Thr-D-Ser
(95) and then the two constituent parts were connected and deprotected yielding
10 (121).
42 H. Budzikiewicz

BocNH OH BocNH OH

N O OH OH
N
91 92

H2N OBn BocNH OH

N OBn N OH
94 93

OBn OBn
H O H
N N OBn
H2N N
O H O
OBn OBn
N
95
+
OH TBS TBS TBS
O O O O
OH 6 5
3 OMe
H2N
HN O
O
89 OBn 90

OH HO
OH OH OH O H O H
N N OH
N N
HN H O H O
O OH N OH
OH
10

Chart 6. Synthesis scheme of anachelin H (10)

8.2. Alterobactin (26)

Several building blocks were prepared separately (Chart 7). Methyl trans-cinnamate
gave by Sharpless enantiocontrolled dihydroxylation a diol from which by a series
of stereo- and regioselective transformations (96) and Ru-catalyzed oxidation for
transformation of the phenyl into a carboxyl group accompanied by adequate protec-
tion (97) and deprotection steps the protected OHAsp derivative 98 was obtained.
The protected (S)-4,8-diamino-3-oxooctanoic acid 99 was reduced with NaBH4,
the resulting mixture of diastereomers was separated and the (3R,4S)-product was
derivatized with benzylated DHB (100). Then derivatized D-Ser-Gly was added and
the serine OH-group was esterified with the protected OHAsp (101). The Gly
carboxyl group was finally set free.
Microbial Siderophores 43

NHBoc NHBoc NHBoc

COOMe COOMe COOBzl
Ph ButOOC HOOC
96 97 98
OAc OAc OTBS

O
BocNH COOEt
99 NHCbz
OBzl
OBzl
OTBS
H
N COOH

O 100 NHCbz
OTce

OBzl O
OBzl O NH
TBSO O NHBoc
H
N O COOOBzl
N
O 101 NHCbz H O OTBS
+
H
N NHMtr

NH

O
BocNH O
HN OTce
102 N
H O
TBSO COOBzl

OH

OH OH
CO-NH-(CH2)4-CH-CH-CH2-CO-Ser-Gly-Arg-β-OHAsp-Gly-β-OHAsp

NH2 26

Chart 7. Synthesis scheme of alterobactin (26)

The synthesis of the remaining part of the molecule started from a condensation
of protected Gly with the OHAsp derivative 98, and subsequently with protected
Arg (102). In the resulting protected tripeptide the Boc group from the Arg residue
was removed. Connection of the two building blocks between Gly and Arg
was followed by ring closure between Ser and Gly. Deprotection yielded finally
alterobactin (26) (83).
44 H. Budzikiewicz

8.3. Parabactin (44)

Here the critical step is the formation of the oxazoline ring. Both the stereochemistry
of the two chiral centers and its acid lability had to be considered. Two approaches
have been published. They can be modified for other members of this class.
The terminal NH2-groups of N5-benzylspermidine (Chart 8) were acylated with
2,3-dimethoxybenzyol chloride and the benzyl group was removed by hydrogeno-
lysis (28b). N1, N10-bis(2,3-dimethoxy)benzoylspermidine (103) was then reacted
with protected L-threonine (104). The Boc group was removed with CF3COOH
and the methoxy groups were cleaved with BF3 (105). Subsequent reaction with
2-hydroxybenzimidoethyl ether (106) gave parabactin (44) (28, 28c).
In the second synthesis (Chart 9) of 44 the carboxyl group of benzoyl-protected
salicylic acid was activated by transformation into the 1,2-thiazolidine-2-thione
derivative 107 and reacted with D-threonine. The methyl ester was debenzoylated
reductively (108). Treatment with SOCl2 resulted in cyclization accompanied by
stereoinversion of Cb of threonine. The resulting cis-oxazoline derivative 109
was epimerized at Ca with C2H5ONa. Subsequent hydrolysis of the ester function
gave the trans-carboxylic acid 110 which was reacted with N1, N10-bis(benzyloxy-
carbonyl)spermidine by treatment with phenylbis-(2-thioxo-1,3-thiazolidine-3-yl)
phosphinoxide (111). The remaining steps leading to 44 (removal of the N-protecting

O
O O
+ Boc-NH-CH-COO-N
O H O H3C-CHOH
CO-NH-(CH2)3-N-(CH2)4-NH-CO O

103 104

OH H2N.HBrOH OH
+
OH CO OH OH
CO-NH-(CH2)3-N-(CH2)4-NH-CO HN OC2H5
105 106

OH

OH N O OH

OH CO OH
CO-NH-(CH2)3-N-(CH2)4-NH-CO
44

Chart 8. Synthesis I of parabactin (44)

Microbial Siderophores 45

OBzl OH OH
S
O HN O N O
N S H
H3COOC OH H3COOC
107 108 109

OH OH
N O N O

OCH2Ph CO OCH2Ph HOOC

110
CO-NH-(CH2)3-N-(CH2)4-NH-CO
111

OH
N O
OH OH

OH CO OH
CO-NH-(CH2)3-N-(CH2)4-NH-CO
44

Chart 9. Synthesis II of parabactin (44)

groups, reaction with 2,3-diacetoxybenzyl chloride and cleavage of the acetoxyl

groups) were standard operations (255).
In a recent modification of the second synthesis (308) effected for fluvibactin
(45) an o-xylene protection group was proposed (reaction of 2,3-dihydroxy-
benzoic acid methyl ester with 1,2-di(bromomethyl)benzene) which could
be removed later by hydrogenolysis. The formation of the oxazoline ring from
protected DHB-L-threonine methyl ester was achieved with Mo(VI) catalysts
(e.g. (NH4)2MoO4) without affecting the chiral centers. Derivatization of the
primary amino groups of norspermidine with the protected DHB methyl ester
was catalyzed by Sb(OC2H5)3.

8.4. Nannochelin A

For the condensation with the properly derivatized lysine part (112) 30 -tert-butyl-
1,5-di-N-hydroxysuccinimidyl citrate (113) was used (Chart 10). It was prepared
from 1,5-dimethyl citrate by reaction with tert-butyl acetate, alkaline hydrolysis of
the methyl ester and coupling with N-hydroxysuccinimide by DCCI (237).
46 H. Budzikiewicz

H COOMe

BocHN NH2
114

H COOMe
O C6H5
BocHN N
115 H O

H COOMe
O C6H5
BocHN N
O
C6H5 O
116
CO-OSuc
H COOMe OH
OH
H2N N +
COOtBu
C6H5 O CO-OSuc
112
113

H COOMe O
CO-NH N C6H5
OH OH

COOH OH
CO-NH N C6H5

H COOMe O

54-dimethyl ester

Chart 10. Synthesis of nannochelin A (54-dimethyl ester)

For the synthesis of the lysine part (112) N2-Boc-L-lysine methyl ester (114)
was treated with benzoylperoxide/Na2CO3 (115) and subsequently with trans-
cinnamoyl chloride yielding 116. The hydroxamate ester was deprotected with
NH3/CH3OH at
23 C and the Boc group was removed with CF3COOH. Conden-
sation with the citric acid 3-tert-butyl ester was effected with (C2H5)3N. After cleav-
age of the ester with CF3COOH nannochelin A (54-dimethyl ester) was obtained
(29). The difficulties in the synthesis lay in the various functional and protecting
groups, which had to be introduced and removed in a deliberate sequence.

8.5. Pyochelin

The problem encountered with all published syntheses (6, 301, 397) is the non-
stereospecific formation of C-40 and the facile conversion of C-200 . The common
approach (Chart 11) consists in the reaction of 2-hydroxybenzonitrile (117) with
Microbial Siderophores 47

OH NH2 OH
+ COOH
HS
N H N COOH
117 118 119 S

N N
CHO CO-N
S S
121 120 O

OH

N COOH
N
4' 2" 4"
S
S
66-stereoisomers

Chart 11. Synthesis of pyochelin stereoisomer mixture

L-cysteine (118) giving dihydroaeruginoic acid (119), reduction of the carboxyl

group to the aldehyde 121 and condensation of the latter with L-N-methyl-cysteine.
Details will be given for the procedure worked out by Zamri and Abdallah (397).
The first condensation step was effected in a phosphate buffer (pH 6.4) to minimize
epimerization at C-40 . Then the carboxyl group was reacted with N,O-dimethyl-
hydroxylamine (120) using diethylcyanophosphonate as condensation agent.
Reduction with LiAlH4 yielded the aldehyde 121, which then was treated with
0 00 00
L-N-methyl-cysteine. A mixture of the four stereoisomers of (66), (4 R,2 S,4 R),
0 00 00 0 00 00 0 00 00
(4 S,2 S,4 R), (4 R,2 R,4 R), (4 S,2 R,4 R) in a ratio of 2:1:2:5 was obtained.

9. Epilog

The history of siderophores actually began towards the end of the nineteenth
century when laboratories engaged in bacteriological research observed that cer-
tain bacterial cultures showed a green fluorescence, and when in 1891 the first
attempts were reported to isolate the fluorescent pigment (later namend pyoverdin,
Sect. 2.1) produced by Bacterium fluorescens liquefaciens (Pseudomonas fluo-
rescens), although it was not before 1978 that J.-M. Meyer demonstrated its being
involved in the iron transport into the bacterial cell (37). Pyoverdins were among the
centers of interest during the last decades, and other preferred topics were the fungal
siderophores (Sect. 2.6), and more recently the marine lipopeptides (Sect. 2.8).
This review is mainly concerned with structural aspects of siderophores and
their iron transport, intended to give a status report of what has been achieved up to
late-2009. But the fields of interest in siderophores are much wider, spreading into
– genetics (identification of the genes responsible for the synthesis of the side-
rophores and their receptors (e.g. (403, 409)),
48 H. Budzikiewicz

– medicine (siderophores as virulence factors (e.g. (75)), but serving also as

carriers for antibiotics in a Trojan Horse strategy (e.g. (35a)),
– agriculture (starving phytopathogenic bacteria by binding iron (e.g. (187b,
406)),
– environmental problems (binding heavy metal ions (e.g. (90a)), degrading
detrimental compounds (e.g. (205a)), mobilizing uranium and trans-uranium
elements in contanimated soils (e.g. (242a)),
just to mention some areas. The diversity of scientific journals to be found in the
References Section gives an idea of where information on siderophores can be
hidden.
Structural work may take its time. Examples are Pseudomonas mendocina
(Sect. 2.9) where the first structural data were reported in 2000 and the next
pertinent publication appeared in 2008, or Legionella pneumophila (Sect. 4.5)
whose legiobactin was first characterized in 2000, further details followed in
2007 and 2009, with loose ends in both cases. Only partially characterized side-
rophores are mentioned wherever data were available in order to stimulate further
work. This would be worthwhile: siderophore research is a fascinating branch of
natural products chemistry promising sometimes surprising results (e.g. (311, 388)).

Acknowledgement Many thanks are due to Dr. J. Neudörfl for preparing the Plates with side-
rophore X-ray structures. Data bases for the X-ray structures: Plate 1: FEPSBC 10; 3: TEQKQV;
4: YELJOP; 5: VENPAC; 6: CUHGUH.

Appendix

Table 7. Pyoverdins Isolated from Pseudomonas spp.

P. Name Peptide chaina,b,c,d Masse Referencesf
(a) Complete or fairly complete structures
Pyoverdins with a C-terminal cOHOrn
6 amino acids
f Ps (= B10h) eLys-OHAsp-Ala-aThr-Ala-cOHOrn 989 (352–354)
f Py 9AWn Ser-Lys-OHHis-aThr-Ser-cOHOrn 1043 (42)
ap Py 4al (= Py SB83) Ala-Lys-Thr-Ser-AcOHOrn-cOHOrn 1046 (47)
p iPy BTP1 Asp-Ala-Asp-AcOHOrn-Ser-cOHOrn 1047 (168)
7 amino acids
f Py PL7 Ser-AcOHOrn-Ala-Gly-aThr-Ala- 1046 (16)
cOHOrn
f Py BTP2 Ser-Val-OHAsp-Gly-Thr-Ser-cOHOrn 1049 (270)
p Py G4R Asp-Orn-(OHAsp-Dab)-Gly-Ser- 1073 (33, 309)
cOHOrni
Py 2908 Ser-Orn-OHAsp-Ser-Ser-Ser-cOHOrn 1088 (373)
ae Py T IIg (=27853) Ser-FoOHOrn-Orn-Gly-aThr-Ser- 1091 (350)
cOHOrnbb
f Py PL8 Lys-AcOHOrn-Ala-Gly-aThr-Ser- 1103 (16)
cOHOrn
Microbial Siderophores 49

Table 7. (continued)
P. Name Peptide chaina,b,c,d Masse Referencesf
p Py 11370 Asp
eLys-OHAsp-Ser-Ala-Ser- 1106 (48)
cOHOrn
p iPy 90-33 Asp-Lys-Thr-OHAsp-Thr-aThr- 1164 (345)
cOHOrn
8 amino acids
p Py 90-51 Asp-eLys-OHAsp-Ser-Gly-aThr-Lys- 1234 (343)
cOHOrn
9 amino acids
c, au Py Pauu Ser-AcOHOrn-Gly-aThr-Thr-Gln-Gly- 1277 (21)
Ser-cOHOrn
f Py 2392 (= A6h) Lys-AcOHOrn-Gly-aThr-Thr-Gln-Gly- 1318 (23)
Ser-cOHOrn
p Ps 589Ao Asp
eLys-OHAsp-Ser-Thr-Ala-Glu- 1336 (279)
Ser-cOHOrn
p Py 2461 (=L1h, Asp-eLys-OHAsp-Ser-aThr-Ala-Thr- 1349 (365)
WCS358h) Lys-cOHOrncc
ap Py 3bt Asp-(AcOHOrn-Dab)-Thr-Ala-Thr-Thr- 1358 (349)
Gln-cOHOrn
10 amino acids
aa
f Py 2798 (=W ) (Ser-Dab)-Gly-Ser-OHAsp-Ala-Gly- 1187 (78)
Ala-Gly-cOHOrn
f Py 17400 Ala-Lys-Gly-Gly-OHAsp-(Gln-Dab)- 1299 (77)
Ser-Ala-cOHOrni
p Py 1,2 Ser-Thr-Ser-Orn-OHAsp-(Gln-Dab)- 1405 (130)
Ser-aThr-cOHOrn
f Py 1.3 Ala-Lys-Gly-Gly-OHAsp-(Gln-Dab)- 1285 (125)
Gly-Ser-cOHOrn
t Py 2192 Ser-Lys-Ser-Ser-Thr-Ser-AcOHOrn- 1424 (78)
Thr-Ser-cOHOrn
p iPy 90-44 Asp-Lys-AcOHOrn-Thr-Ser-Ser-Gly- 1408 (344)
Ser-Ser-cOHOrns
11 amino acids
f Py 51W Ala-Lys-Gly-Gly-OHAsp-Gln-Ser-Ala- 1375 (371)
Gly-aThr-OHOrn
a
In part (a) D-amino acids are underlined; a broken line indicates either that the stereochemistry of
the amino acid has not been determined or that a specific amino acid occurs both in the D- and the
L-form, but a localization of the the two enantiomers has not been effected. In part (b) D-amino
acids are indicated only when data are available from the literature
b
Abbreviations: P, Pseudomonas; ae, aeruginosa; ap, aptata; as, asplenii; au, aureofaciens; c,
costantinii; ci, cichoriae; en, entomophila; f, fluorescens; li, libanensis; m, marginalis; mo,
monteilii; p, putida; pa, palleroniana; r, rhodesiae; s, syringae; t, tolaasii; Ps, pseudobactin; Py,
pyoverdin; iPy, isopyoverdin; amino acids: 3-letter code - in addition: OHAsp, threo-b-hydroxy-
Asp; OHHis, threo-b-hydroxy-His; OHOrn, N5-hydroxy-Orn; Ac(Fo,Bu)OHOrn, N5-acetyl (for-
myl, (R)-b-hydroxy-butyryl) OHOrn; cOHOrn, cyclo-OHOrn (3-amino-1-hydroxy-piperidone-2);
aThr, allo-Thr
c
Amino acids are bound to the chromophore or to the preceding amino acid by their a-amino group
or in the case of Lys occasionally by its e-amino group (indicated as eLys)
50 H. Budzikiewicz

Table 7. (continued)
P. Name Peptide chaina,b,c,d Masse Referencesf
12 amino acids
f Py GM Ala-Lys-Gly-Gly-OHAsp-Gln-Ser-Ala- 1430 (242)
Ala-Ala-Ala-cOHOrn
Py 1547 Ser-Lys-Ala-AcOHOrn-Thr-Ala-Gly- 1547 (304)
Gln-Ala-Ser-Ser-OHOrn
Pyoverdins with a C-terminal cyclo-tetra- or tripeptide
cyclo-tetrapeptide
f Py G173 Ser-Ala-AcOHOrn-(Orn-Asp- 1175 (363)
AcOHOrn-Ser)
Py 96-312 Ser-Ser-FoOHOrn-(Lys-FoOHOrn-Lys- 1190 (315)
Ser)
Py 96.188 Ser-Lys-FoOHOrn-(Lys-FoOHOrn-Glu- 1232 (379)
Ser)
ae Py C-E (= PAO1h, Ser-Arg-Ser-FoOHOrn-(Lys-FoOHOrn- 1333 (35, 81)
ATCC 15692, Pa) Thr-Thr)
Py 95-275 (= BTP7h) Ser-Ser-FoOHOrn-Ser-Ser-(Lys- 1364 (342)
FoOHOrn-Lys-Ser)
f Py 12 Ser-Lys-Gly-FoOHOrn-Ser-Ser-Gly- 1520 (124)
(Lys-FoOHOrn-Glu-Ser)
cyclo-tripeptide
f Py 13525m Ser-Lys-Gly-FoOHOrn-(Lys-FoOHOrn- 1160 (146)
Ser)
pa Py 96-318 Ser-Orn-FoOHOrn-Ser-Ser-(Lys- 1263 (315)
FoOHOrn-Ser)
f Py 18-1 Ser-Lys-Gly-FoOHOrn-Ser-Ser-Gly- 1391 (3)
(Lys-FoOHOrn-Ser)
Pyoverdins with a C-terminal cyclodepsipeptide or a free carboxyl group
6 amino acids
a PS 6.10 Ala-Orn-OHAsp-Dab-AcOHOrn-Lys 1091 (46)
7 amino acids
ae Py R0 (Ser-Dab)-FoOHOrn-Gln-FoOHOrn- 1046 (305)
Gly
d
Parentheses indicate either a cycle formed by an amide or ester bond between the carboxyl group
of the C-terminal amino acid and a side chain functionality of another amino acid or the
condensation product of the NH2 groups of Dab with the amide carbonyl group of the preceding
amino acid giving a tetrahydropyrimidine ring (see Chart 1)
e
Nominal molecular mass for a Py or iPy chromophore with a succinic acid side chain; the exact
mass is about 0.5 Da higher
f
References to complete structure elucidations. For further details see (37)
g
Probably identical with the pyoverdin of Pseudomonas aeruginosa ATCC 9027 (212)
h
The structure published originally had to be corrected or amended; literature references to the
originally proposed structure may be found in (37)
i
Accompanied by the not cyclized Dab form (M + 18)
j
Accompanied by a non-cyclic pyoverdin with the same amino acid sequence
k
For this pyoverdin an e-amino Lys linkage was claimed but not substantiated. It is probably
identical with the pyoverdin from P. putida 9AW where a a-amino Lys linkage was established
l
P. aptata is a pathovar of P. syringae. The same pyoverdin was found produced by P. fluorescens
SB83 (20). The identification of P. aptata may, therefore, be questioned (cf. also (179))
Microbial Siderophores 51

Table 7. (continued)
P. Name Peptide chaina,b,c,d Masse Referencesf
ci PaB eLys-OHAsp-Thr-(Thr-Gly-OHAsp- 1093 (50)
Ser)
s Py 19310 eLys-OHAsp-Thr-(Thr-Ser-OHAsp- 1123 (179)
Ser)j
ae Py R (=Pa6) (Ser-Dab)-FoOHOrn-Gln-Gln- 1173 (127)
FoOHOrn-Gly
8 amino acids
p Ps A214 (= Ps 39167) Ser-AcOHOrn-Ala-Gly-(Ser-Ala- 1134 (365)
OHAsp-Thr)j
h
f Py P19 (= Ps 7 SR1 , Ser-AcOHOrn-Ala-Gly-(Ser-Ser- 1150 (372)
Ps A 225) OHAsp- Thr)j
ch Py D-TR133 Asp-FoOHOrn-Lys-(Thr-Ala-Ala- 1230 (17)
FoOHOrn-Ala)j,x
f Py I-III Asn-FoOHOrn-Lys-(Thr-Ala-Ala- 1286 (287)
FoOHOrn-Lys)
f CHAO Asp-FoOHOrn-Lys-(Thr-Ala-Ala- 1287 (387)
FoOHOrn-Lys)
9 amino acids
p Py C Asp-BuOHOrn-Dab-Thr-Gly-Ser-Ser- 1370 (319)
OHAsp-Thr
p Py BTP16 Asp-BuOHOrn-Dab-Thr-Gly-Ser-Ser- 1370 (271)
OHAsp-Thr v
10 amino acids
as Py fuscovaginae eLys-OHAsp-Ala-(Thr-Dab-Gly-Gly- 1316 (49a, 231)
Thr-(OHAsp-Dab))
(b) Partial or tentative structures
Pyoverdins with a C-terminal cOHOrn
p Thai (Ser-Dab)-Thr-Ser-AcOHOrn-cOHOrn 1016 (306)
f Py 244k Ser-eLys-OHHis-aThr-Ser-cOHOrn 1043 (132–134)
p Py 12633o Asp-Lys-OHAsp-Ser-Thr-Ala-Glu-Ser- 1336 (80)
cOHOrn
Pyoverdins with a C-terminal cyclo-tetra- or tripeptide
cyclo-tetrapeptide
f D47 Ser-Orn-FoOHOrn-(Lys-FoOHOrn-Glu- 1218 (119)
Ser)
r L25 Ser-Lys-FoOHOrn-Ser-Ser-Gly-(Lys- 1421 (119)
FoOHOrn-Ser-Ser)
m
The same pyoverdin was isolated from P. chlororaphis ATCC 9446 (146) and CNR15 (162). The
reported isolation from P. putida KT2440 (297) is the result of a mix-up of strains (J.-M. Meyer,
private communication)
n
Probably identical also with that from P. fluorescens 244
o
The Py 589A is probably identical with the pyoverdin Py Pp 12633
p
Either the preliminary structural work or the identification of the strains may be questioned since
screening of a large number of P. aeruginosa strains revealed the existence of only three siderovars
characterized by the production of the pyoverdins Py C-E, Py R and Py Pa TII (234) plus probably of
a mutant of Py R (R0 (305)). Py Pa 15152 was shown to be identical with Pa D above (20)
q
The structural proposals are tentative; Orn/Asn and Lys/Gln have the same mass, Lys may be
incorporated in the peptide chain by its a- or its e-amino group
52 H. Budzikiewicz

Table 7. (continued)
P. Name Peptide chaina,b,c,d Masse Referencesf
cyclo-tripeptide
m G 76 Ser-Ser-FoOHOrn-Ser-Ser-(Lys- 1236 (119)
FoOHOrn-Ser)
DSM 50106 Ser-Lys-Gly-FoOHOrn-Ser-Ser-Gly- 1377 (119)
(Orn- FoOHOrn-Ser)
Pyoverdins where only limited mass spectral data are availableq
p Py GS43 Lys-OHAsp-Ser-Ser-Ser-cOHOrn 1007 (231)
li Py 96.195 Ala-Orn-OHAsp-Ser-Orn-Ser-cOHOrn 1091 (231)
Py G 85 Ser-Lys-OHAsp-Ser-Orn-Ser-cOHOrn 1121 (231)
Py G 76 Ser-Ser-FoOHOrn-Ser-Ser-Lys- 1236 (231)
(FoOHOrn-Ser)
Py HR6 Asp-e-Lys-OHAsp-Ser-Ser-Thr-Thr- 1238 (231)
Thr-cOHOrn
LBSA1 Asp-Arg-AcOHOrn-Lys-Ser-Asp- 1260 (231)
cOHOrn
mo iPy Lille 1 Asp-Lys-AcOHOrn-Ala-Ser-Ser-Gly- 1291 (231)
Ser-cOHOrn
f Py G153 Ser-Lys-Ala-Ser-Ser- AcOHOrn-Ser- 1293 (231)
Ser-cOHOrn
en L48 Ala-Asn-Dab-OHHis-Gly-Gly-Ala-Thr- 1298 (219)
Ser-cOHOrn
p Py G172 Ala-Lys-Dab-OHAsp-Thr-Gly- OHAsp- 1335 (231)
Gly-Thr-Thr - H2O
f Pf0-1 Ala-AcOHOrn-Orn-Ser-Ser-Ser-Arg- 1381 (231)
OHAsp-Thr
p 90-136/ G 168 Ser-Lys-Ser-Ser-Thr-Thr-AcOHOrn- 1424 (231)
Ser-Ser-cOHOrn
IB3 Ser-Ala-Thr-Gln-Orn-AcOHOrn-Thr- 1764 (231)
Thr-Ala-Ser-Thr-Ala-Ala-cOHOrn
Various pyoverdins with incomplete structural data
ae Py UNKp Ser-Thr-Ser-Gly-OHOrn-OHOrn (107)
ae Pa 15152p 2 Arg, 2 Orn, 3 Ser, 3 Thr (107)
p Py Pm OHAsp, Lys, OHOrn, 2 Ser, 3 Thr (212a)
s Py Ps Lys, OHOrn, 3 Ser, 3 Thr (362)
s Py PSSz 2 OHAsp, Lys, 2 Ser, 2 Thr (68)
P. mildenbergii Glu, Lys, Ser, Thrw (259)

r
The reported amino acid composition cannot be correct. The minimum molecular mass calculated
from it is about 120 u higher than the molecular mass determined by mass spectrometry. Also the
amino acids acting as ligands for Fe3+ are missing
s
2 D-Ser, 2 L-Ser
t
Contains 2 Thr and one aThr. The amino acid analysis of the corresponding ferribactin gave
D-Ala, L-Asp, L-Dab, D- and L-Glu, L-Orn, D-aThr, L-Thr and D-Tyr
u
The same pyoverdin was isolated from P. tolaasii NCBBP 2192 (P. constantinii); the fact that the
strain designated as P. aureofaciens does not produce phenazines casts doubts on the correct
identification (364)
v
1 Thr, 1 aThr
w
Ratios of 1:1:2:4 and 1:2:3:5 are reported for the pyoverdins from two strains of P. mildenbergii;
for the second one a blocked N-terminus was demonstrated
x
1 D-Ala, 2L-Ala; the pyoverdin D-TR 133 is accompanied by a small amount of a pyoverdin where
the second Ala is replaced by Gly
Microbial Siderophores 53

Table 7. (continued)
P. Name Peptide chaina,b,c,d Masse Referencesf
p Py A1 Asx, Glx, 3 Gly, His, Lys, 4 Ser, Thr, (32)
Valr
f BTP9y 2 Lys, 2 FoOHOrn, 5 Ser (269)
p BTP14aa Asx, Dab, Glx, Gly, Orn, 2 Ser, Thr, (269)
aThr
y
Probably identical with the pyoverdins of BTP7 and BTP16 (private communication
Dr. M. Ongena, Liège)
z
Probably identical with the pyoverdin Py 19310
aa
Identical with pyoverdin W mentioned in (79) (private communication Dr. J.-M. Meyer, Strasbourg)
bb
Accompanied by a variety with one AcOHOrn (187a)
cc
Accompanied by a small amount of a pyoverdin where Ala is replaced by Gly

Notes Added in Proof

Section 2.5

Coelichelin from Streptomyces coelicolor comprises D-N5-formyl-N5-hydroxy-

Orn-D-aThr bound to N5 of L-N5-hydroxy-Orn whose N2 is acylated by D-N5-
formyl-N5-hydroxy-Orn (412).

Section 2.6

Erythrochelin from Saccharopolyspora erythraea is a coprogen-type siderophore

(Table 2) with Ac1 ¼ i and Ac2 ¼ D-Ser-D-N2, N5-diacetyl-N5-hydroxy-Orn (413).

Section 2.7

The transport system of Bacillus subtilis accommodates the Fe3+ complexes of

enterobactin (D-configured), enantio-D-enterobactin and of corynebactin (bacilli-
bactin) (both L). Since only L complexes can be bound to the receptor a configu-
rational change from D to L is induced. Only the natural ferri-L-siderophores can be
degraded enzymatically (399, 408).
From Nocardia tenerifensis the heterobactin JBIR-16 was obtained (30, R ¼ DHB).
The stereochemistry of the two Orn residues was not established. By mass spectrometry
a 1:1 Fe3+/Lig ratio was determined for the red complex (407).

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Resin Glycosides from the Morning Glory
Family

Rogelio Pereda-Miranda, Daniel Rosas-Ramı´rez, and Jhon Castañeda-Gómez

Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
2. Ethnobotanical Background and Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
3. Structural Diversity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
3.1. Chemical Composition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
3.2. Resin Glycosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
4. Isolation Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
5. Structure Elucidation of Resin Glycosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
5.1. Degradative Chemical Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
5.2. Spectroscopic Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
5.3. Crystallographic Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
5.4. Molecular Modeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
6. Strategies for Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
6.1. Tricolorin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
6.2. Ipomoeassin E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
6.3. Woodrosin I . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
7. Significance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
7.1. Traditional Medicine and Morning Glories . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
7.2. Biological Activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
7.3. Pharmacology and Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
7.4. Chemical Ecology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147

R. Pereda-Miranda
Departamento de Farmacia, Facultad de Quı́mica, Universidad Nacional Autónoma de México,
Ciudad Universitaria, 04510 DF, México
e-mail: [email protected]
D. Rosas-Ramı́rez
Departamento de Farmacia, Facultad de Quı́mica, Universidad Nacional Autónoma de México,
Ciudad Universitaria, 04510 DF, México
e-mail: [email protected]
J. Castañeda-Gómez
Departamento de Farmacia, Facultad de Quı́mica, Universidad Nacional Autónoma de México,
Ciudad Universitaria, 04510 DF, México
e-mail: [email protected]

A.D. Kinghorn et al. (eds.), Fortschritte der Chemie organischer Naturstoffe / 77

Progress in the Chemistry of Organic Natural Products, Vol. 92,
DOI 10.1007/978-3-211-99661-4_2, # Springer-Verlag/Wien 2010
78 R. Pereda-Miranda et al.

Plate 1. Ethnobotany and Background. Convolvulaceae, the botanical name for the morning
glory family, derives from the Latin convolvo, referring to its growth of intertwining vines
(A: Heavenly blue, Ipomoea tricolor). The purgative properties of the Mexican roots were readily
accepted in Europe when introduced in the sixteenth century, since pre-Christian folk tradition
had already proclaimed the virtues of skammonia as found in Dioscorides’ work De Materia
Medica, ca. 50–68 A.D.
Resin Glycosides from the Morning Glory Family 79

1. Introduction

Resin glycosides are part of a very extensive family of secondary metabolites

known as glycolipids or lipo-oligosaccharides and are constituents of complex
resins (glycoresins) (1) unique to the morning glory family, Convolvulaceae (2).
These active principles are responsible for the drastic purgative action of all the
important Convolvulaceous species used in traditional medicine throughout the
world since ancient times. Several commercial purgative crude drugs can be
prepared from the roots of different species of Mexican morning glories. Their
incorporation as therapeutic agents in Europe is an outstanding example of the
assimilation of botanical drugs from the Americas as substitutes for traditional Old
World remedies (3). Even though phytochemical investigations on the constituents
of these drugs were initiated during the second half of the nineteenth century, the
structure of their active ingredients still remains poorly known for some examples
of these purgative roots. During the last two decades, the higher resolution cap-
abilities of modern analytical isolation techniques used in conjunction with power-
ful spectroscopic methods have facilitated the elucidation of the active principles of
these relevant herbal products.
This chapter describes the ethnobotanical information associated with the pur-
gative morning glory species and how traditional usages were instrumental in plant
selection for chemical studies. The advantages and limitations of available analyti-
cal techniques for the isolation, purification, and structure characterization of the
individual constituents of these complex glycoconjugates are also discussed. Struc-
ture elucidation has been conducted on resin glycoside mixtures of 34 convolvula-
ceus species pertaining to the subfamily Convolvuloideae, with the exception of
Cuscuta (two species), and include five genera: Ipomoea (23 spp.), Merremia (three
spp.), Convolvulus (three spp.), Operculina (two spp.), and Calystegia (one sp.).
A reliable compilation of the structures of the individual resin glycosides and their
glycosidic acid derivatives known to date is provided.

2. Ethnobotanical Background and Discovery

The botanical name Convolvulaceae for the morning glory family derives from the
Latin convolvo, meaning interlaced, and describes a growth pattern of intertwining
vines wrapping around a support, and is characteristic of the majority of the species
<
Plate 1. (continued) (B: Skammonia, Convolvulus scammonia; Juliana Anicia Codex, Vienna,
Österreichische Nationalbibliothek, Cod. med. gr. I, fol. 331v). The jalap root was the main
purgative ingredient in pre-Hispanic herbal medicine (C: Ipomoea purga, the Latin description of
this illustration in the Badianus Manuscript reads Purgatio ventris, “to purge the stomach”; Libellus
de Medicinalibus Indorum Herbis, 1552. Fol. 32r. CONACULTA-INAH-MEX, with permission of
the “Instituto Nacional de Antropologı́a e Historia”, Mexico) and launched the continuing major
commercial enterprises between the Americas and Europe. The Indian Rhubarb in herbals also
known as “root of Michoacan” (Ipomoea jalapa) became a New World substitute for the drastic
purgative scammony because of its milder effects (D: I. jalapa. Gerald’s Herbal. London. J.
Norton, 1597. Dover. Reproduced from reference (7) with permission of Dover Publications, Inc.)
80 R. Pereda-Miranda et al.

Plate 2. Jalap (“Rhizoma Jalapae”), the root of Ipomoea purga. The root of this evergreen vine
(A: Traditional production system in Central Veracruz, Mexico) is one of several distantly related
tuberous New World Ipomoea species, including I. orizabensis, I. stans, I. jalapa, and I. simulans,
which are the source of a group of valued purgative remedies known as “jalaps”. The therapeutic
benefits were recognized early as illustrated by this eighteenth century illustration (B: Juan
Navarro’s Natural History. Historia Natural o Jardı́n Americano, a manuscript of 1801 fol. 211,
with permission of UNAM). Fresh and darker smoke-dried roots of “Rhizoma Jalapae” (C) of which
the drug consists. Examples of the fragmented roots into which they are offered commercially (D)
Resin Glycosides from the Morning Glory Family 81

(Plate 1). The most noticeable anatomical characteristics of this family are the
presence of cells in foliar and floral tissues, seeds, and the periderm of tuberous
roots, which secrete glycoresins. The ethnopharmacological knowledge of plant
containing-resin glycosides strongly influenced early phytochemical investigation
and the discovery of these bioactive principles. In Mesoamerica, purgative remedies,
known to the pre-Hispanic Aztecs as “cacamotli tlanoquiloni”, consisted of diverse
kinds of tuber-shaped roots, which varied in morphological characteristics, habitat,
and potency of effects. Contemporary investigations have identified these roots as
belonging to the genus Ipomoea, currently recognized as I. purga, I. orizabensis,
I. stans, and I. jalapa, together with a few others less often used. The Spanish colonists
took notice of these perennial, herbaceous bindweeds with cathartic, acrid-tasting,
and resin-producing roots because their purgative properties were important to
sixteenth century European galenic medicine (4, 5). These Mexican purgative roots
were readily accepted as a New World succedaneum of scammony (Convolvulus
scammonia), an Eastern Mediterranean herb, known in English as Syrian or purging
bindweed, which had been used since pre-Christian times (6). In addition, several
field (Convolvulus arvensis), hedge (C. sepium), and sea (Calystegia soldanella)
bindweed types were likewise extensively documented in European herbals for their
purgative properties.
In fact, a major commercial enterprise was launched between the Americas
and Europe that continues to this day from the introduction to the Old World of
the so-called “root of Michoacan”, named after the Western province of New Spain
where it was thought to have been originally found and known in English herbals as
“rhubarb of the Indies” (7). The mild effects of this new drug gained a rapid and
widespread acceptance in Europe, as well as being subsequently viewed and known as
a panacea (8). The precise identification of this root is still much disputed, although it
is now generally agreed that it is I. purga (Plate 2). In recognition of its important
benefits, the colonists bestowed the vernacular name “Jalapa” on this signature
species (“officinal jalap” or “Rhizoma Jalapa”), for they found it in abundance in
the tropical region of Xalapa, in the state of Veracruz. A second purgative root
likewise restricted to the tropical areas in the Gulf of Mexico, “Orizaba jalap”,
identified as I. orizabensis, often has been used as a substitute or adulterant for the
true jalap, producing a moderately strong cathartic. Even today, this root is referred
to as false jalap or Mexican scammony. The jalap medicinal plant complex included
“jalapa hembra” or “oficinal” (I. purga), “jalapa macho” (I. orizabensis) and “jalapa
de Tampico” (I. simulans) (9), although in the ethnobotany of the neotropical and
Indomalayan ecozones, several morning glories belonging to the genera Ipomoea,
Merremia, and Operculina are also employed.
The cathartic crude drugs are derived from the roots, which are rich in glycore-
sins (10–18% dry weight), and provoke peristaltic movements in the small intes-
tine. Pharmaceutical products come in the form of liquid alcoholic extracts, root or
resins powders that are consumed singly or in combination with other ingredients to
modify the therapeutic effect (10). Once the demand for these roots declined due to
various reasons, German and Italian herbalists introduced to the world market other
plants such as Brazilian-grown jalap, I. operculata (syn. Operculina macrocarpa),
82 R. Pereda-Miranda et al.

and “Indian jalap”, the roots of Ipomoea turpethum (syn. O. turpethum), which are
available as milder but still very effective laxatives.
Phytochemical reports for jalap root were published as early as the second
half of the nineteenth century (2), although most of the botanical and chemical
descriptions found in the literature up to even recently are confusing and not
scientifically reliable. The structural complexity of the resin glycosides seriously
hampered the isolation of individual analogues limiting these chemical studies to
the characterization of only their products of chemical degradation (11). Resin
glycosides were seen as very large, high molecular weight polymers of oligosac-
charides glycosidically linked to a hydroxylated fatty acid (12). In the 1980s, the
application of high-performance liquid chromatography (HPLC) led to the isola-
tion of four pure natural constituents from a resin glycoside mixture for the first
time. They were collectively called orizabins from the Mexican scammony
(I. orizabensis), their supposed source (13). The use of contemporary techniques
such as high-field nuclear magnetic resonance (NMR) and high-resolution mass
spectrometry (MS) allowed for the structure characterization of the above-men-
tioned compounds as individual macrolactones of a distinctive glycosidic acid and
forced the rethinking of the long sustained hypothesis of a polymeric structure for
this class of compounds.

3. Structural Diversity

3.1. Chemical Composition

Resin glycosides are glycosyl derivatives of monohydroxy and dihydroxy C14 and
C16 fatty acids. Their structures are unusual for they are amphipatic metabolites,
meaning that their structure contains hydrophobic (fatty acid aglycones) as well as
hydrophilic (sugar or glycone) moieties. The latter are composed by a heteropoly-
saccharide of only a few residues (up to six), which are of no more than four
different monosaccharides. Sugar units found in these metabolites are D-glucose
and epimers of pentoses (L-rhamnose, D-fucose, D-quinovose, and D-xylose) in their
pyranose forms. The O-glycosidic linkage is the only type connecting the mono-
saccharide residues between each other and with the aglycone. L-Rha-(1!2)-D-Fuc,
L-Rha-(1!4)-L-Rha, and D-Glc-(1!2)-D-Fuc moieties represent highly conserved
disaccharide subunits. The structural complexity arises from the variable linkage
positions as (1!2), (1!3), (1!4), and (1!6). Short-chain aliphatic acids,
e.g., acetic (ac), propionic (pa), n-butyric (ba), isobutyric (iba), (2S)-methylbutyric
(mba), 3-methylbutyric (3-mba), ()-(2R,3R)-3-hydroxy-2-methylbutyric (nilic acid,
nla), and tiglic (tga) acids, arylalkyl acids such as (E)-cinnamic acid (ca), and
Resin Glycosides from the Morning Glory Family 83

saturated fatty acids with different chain lengths, e.g., n-hexanoic (hexa) or caproic,
n-octanoic (octa) or caprylic, n-decanoic (deca) or capric, n-dodecanoic (dodeca) or
lauric, n-hexadecanoic (hexadeca) or palmitic, n-octadecanoic (octadeca) or stearic,
and n-eicosanoic (eicosa) or arachidic acids, are among the most frequently found
ester substituents linked to the oligosaccharide cores. Most of them contain jalapi-
nolic acid, (11S)-hydroxyhexadecanoic acid, as the aglycone, which is always
arranged to form a macrolactone ring spanning two or more units of their saccharide
backbones. The chemical diversity of these oligosaccharides is further increased
by the diverging possibilities of cyclization of the glycosidic acid cores into cor-
responding macrolactones. In addition, the multiple variations caused by acylation
considerably increase their structural variety. In fact, on the whole, a large number of
resin glycoside congeners occur in the Convolvulaceae family as well as a remark-
able number in each species.

3.2. Resin Glycosides

The presence of resin glycosides in Convolvulaceous plants has been established

through two approaches. The first one was by means of an ethnomedical rationale
associated with the laxative properties of the herbal drugs (3). The second one was
the isolation of the crude resins and the identification of their hydrolysis products
(2), mainly through isolation of the glycosidic acid produced under saponification
(10). Resin glycosides were classified into two groups based on their solubility in
ether: jalapin (soluble) and convolvulin (insoluble). The jalapin group shares the
common structure of a macrolactone composed by one acylated glycosidic acid.
Members of the convolvulin group possess larger molecular weights, which could
be a result of being oligomers of glycosidic acids (12).
Up to now, Convolvulaceae resin glycosides have not been reviewed per se but
have been included in two reviews (2, 11). The latest is not comprehensive,
dealing only with the structural composition of resin glycosides through their
products of hydrolysis (2). Since 239 of these compounds are presently known, a
comprehensive review is presented in this chapter. The chemical diversity of
these resin glycosides has been divided into groups based on the size of their
oligosaccharide cores, thus imposing a logical sequence of structural complexity
among congeners and listed in alphabetical order. To date, 53 different glycosidic
acids have been identified, of which a large number have been accorded trivial
names based on their plant source. In the present review, individual glycosidic
acids are named according to the rules established by the Chemical Abstracts
Service and only the structures for intact resin glycosides are presented. They are
not IUPAC names but clearly describe the fragments of which each oligosaccha-
ride is composed. For example, the correct IUPAC name for compound 1 would
be (2R,3R)-((3S,4S,4aR,16S,17aR)-2-methyl-6-oxo-16-propyl-4-((2S,3R,4S,5R)-3,
84 R. Pereda-Miranda et al.

4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yloxy)hexadecahydropyrano-[3,2-
b][1,4]dioxacyclopentadecin-3-yl)-3-hydroxy-2-methylbutanoate.

3.2.1. Disaccharides

Cuscutic Resinoside A

Cuscutic resinoside A (1; tetradecanoic acid, (11S)-[[6-deoxy-3-O-(6-deoxy-

a-L-mannopyranosyl)-4-O-[(2R,3R)-3-hydroxy-2-methyl-1-oxobutyl]-a-L-manno-
pyranosyl]oxy]-intramol. 1,20 -ester) was obtained from the ethyl acetate-soluble
fraction of a methanol extract prepared from the seeds of Cuscuta chinensis Lam.
The purification of this compound employed a combination of column and prepar-
ative-scale HPLC. The structure was deduced from spectroscopic evidence and
acid hydrolysis (14). The degradative process gave convolvulinolic acid, nilic
acid, and L-rhamnose. The sugar components were identified by GC analysis
after being converted to their thiazolidine derivatives. This disaccharide has a
unique macrocyclic lactone, which is placed between C-1 and C-2 of the first
rhamnose moiety.

O
O
O
OH O O O

HO O
O
HO OH
1

Ipomoeassins A–F

Six individual disaccharides have been isolated from the glycoresin of the leaves of
Ipomoea squamosa Choisy collected in the Suriname rainforest, ipomoeassins A–F
(2–7). The ethyl acetate-soluble extract was subjected to flash column chromatog-
raphy over C18 silica gel and the fraction successively purified by HPLC on C18 and
phenyl columns. The structures for the ipomoeassin series were elucidated by
spectroscopic data and chemical degradation. The alkaline hydrolysis of ipomoeas-
sin A gave two acids, cinnamic and tiglic acids, identified by GC-CIMS. Acid
hydrolysis also gave the 11-hydroxy-4-oxo-tetradecanoic acid as the aglycone and
two sugars, D-glucose and D-fucose. The absolute configurations of the aglycone
stereogenic centers at C-5 (ipomoeassins C–E) and C-11 (ipomoeassins A and B)
were determined by Mosher’s ester formation (15, 16).
Resin Glycosides from the Morning Glory Family 85

O R1

OR2
O O
O O
O HO R3
O O
O O
O OH

Compound R1 R2 R3
2 H ac CH3
3 H H CH3
4 OH ac CH3
5 Oac ac CH3
6 Oac H CH3
7 H ac C3H7

Muricatin B

Misra and Tewari studied the alcoholic extract from seeds of Ipomoea turbinata
Lag., sub nom. Ipomoea muricata (L.) Jacq., and isolated a resin glycoside named
muricatin A (17, 18). The structures of muricatin A and of its alkaline hydrolysis
product, muricatin B, were not elucidated. Later, Khanna and Gupta found that
muricatin A was actually a resin glycoside mixture, which by alkaline hydrolysis
liberated n-caproic, palmitic and stearic acids, and muricatin B (hexadecanoic acid,
11-[[6-deoxy-4-O-(6-deoxy-a-L-mannopyranosyl)-a-L-mannopyranosyl]-oxy]) as
the glycosidic acid. Acid hydrolysis of this derivative gave L-rhamnose as the
only sugar component and jalapinolic acid as the aglycone (19).

3.2.2. Trisaccharides

Cus-1 and Cus-2

The acylated trisaccharides cus 1 and cus 2 were isolated from the CHCl3-soluble extract
of the seeds of Cuscuta chinensis. The extract was fractionated over Sephadex LH-20
and the fractions rich in resin glycosides were chromatographed by column chromatog-
raphy using normal and reversed phases, followed by preparative HPLC. The oligosac-
charide cores of both cus-1 (8) and cus-2 (9) are composed of two L-rhamnoses and
one D-glucose. Cus-1 (D-glucose, O-6-deoxy-a-L-mannopyranosyl-(1!3)-O-[2(S),
4(2R,3R)]-6-deoxy-4-O-(3-hydroxy-2-methyl-1-oxobutyl)-2-O-(11-hydroxy-1-oxotetra-
decyl)-a-L-mannopyranosyl-(1!2)-6-acetate) has convolvulinolic acid as the aglycone,
86 R. Pereda-Miranda et al.

which is linked at the C-2 of the first rhamnose unit, while cus-2 (D-glucose, O-6-deoxy-
a-L-mannopyranosyl-(1!3)-O-[2(S),4(2R,3R)]-6-deoxy-4-O-(3-hydroxy-2-methyl-1-
oxobutyl)-2-O-(11-hydroxy-1-oxohexadecyl)-a-L-mannopyranosyl-(1!2)-6-acetate)
has jalapinolic acid. Acylation is found at C-4 of the first rhamnose by nilic acid and
at C-6 of glucose by acetic acid. These compounds were characterized as a new
group of resin glycosides since their aglycone hydroxy group at C-11 is not linked
to the oligosaccharide chain (20).
O

O
O
HO
HO
O OH

O O

OH O O O (CH2)nCH3

O O OH
HO
HO
OH

Compound n
8 2
9 4

Cuscutic Acids A1–A3

An ether-insoluble resin glycoside fraction was obtained from the seeds of Cuscuta
australis R. Br. Identification and characterization of the alkaline hydrolysis products
revealed the material to be composed of three glycosidic acids, cuscutic acids A1–A3.
In acid A1 (hexadecanoic acid, (11S)-[(O-6-deoxy-a-L-mannopyranosyl-(1!2)-O-
b-D-glucopyranosyl-(1!2)-6-deoxy-b-D-galactopyranosyl)oxy]) the aglycone is
jalapinolic acid. Two triglycosides with convolvulinolic acid were also identified:
cuscutic acids A2 (tetradecanoic acid, (11S)-[(O-6-deoxy-a-L-mannopyranosyl-
(1!2)-O-b-D-glucopyranosyl-(1!2)-6-deoxy-b-D-galactopyranosyl)oxy]) and A3
(tetradecanoic acid, (11S)-[(O-6-deoxy-a-L-mannopyranosyl-(1!2)-O-b-D-gluco-
pyranosyl-(1!2)-b-D-glucopyranosyl)oxy]). So far, no intact resin glycosides have
been isolated containing these glycosidic acids. It is possible that the glycosidic resin
found in C. australis is a complex mixture of glycosidic ester-type oligomers (up to
heptamers). Their core consists of the above-mentioned cuscutic acids acylated at
various positions (21).

Tricoloric Acid C

Two trisaccharide macrolactones have been characterized from the aerial parts of
Ipomoea tricolor Cav. (syn. Ipomoea violacea L.) (heavenly blue), namely, tricolorins
Resin Glycosides from the Morning Glory Family 87

F (10) and G (11). Tricoloric acid C (hexadecanoic acid, (11S)-[(O-6-deoxy-b-D-

glucopyranosyl-(1!2)-O-b-D-glucopyranosyl-(1!2)-6-deoxy-b-D-galactopyranosyl)‐
oxy]) is the glycosidic acid of tricolorin F and was obtained by the alkaline hydrolysis
of the natural product. It is a linear hetero-trisaccharide of jalapinolic acid formed
by one unit of D-glucose, one D-fucose, and one D-quinovose. The glycosidic acid of
tricolorin G has not yet been obtained in free form. However, the structure of
the oligosaccharide core of this natural product was also characterized by spectro-
scopic analysis as being related to tricolorin C with the difference of containing a
L-rhamnose unit instead of the terminal quinovose. The lactonization in both tri-
colorins F (10) and G (11) was located at C-2 of the terminal sugar unit (22).

OH
O
HO
O
HO
HO O O
HO
O O
HO
HO
O

O
10

OH
O
HO
O
HO
HO O O
HO
O
O
HO
HO
O

O
11

3.2.3. Tetrasaccharides

Cuscutic Acids A–D

Cuscutic acids A (tetradecanoic acid, (11S)-[(O-6-deoxy-a-L-mannopyranosyl-

(1!3)-O-6-deoxy-a-L-mannopyranosyl-(1!2)-O-b-D-glucopyranosyl-(1!2)-b-
88 R. Pereda-Miranda et al.

D-glucopyranosyl)oxy]), B (tetradecanoic acid, (11S)-[(O-6-deoxy-a-L-manno-

pyranosyl-(1!3)-O-6-deoxy-a-L-mannopyranosyl-(1!2)-O-b-D-glucopyranosyl-
(1!2)-b-D-xylopyranosyl)oxy]), C (tetradecanoic acid, (11S)-[(O-6-deoxy-a-L-
mannopyranosyl-(1!3)-O-6-deoxy-a-L-mannopyranosyl-(1!2)-O-b-D-gluco-
pyranosyl-(1!2)-6-deoxy-b-D-glucopyranosyl)oxy]), and D (hexadecanoic acid,
(11S)-[(O-6-deoxy-a-L-mannopyranosyl-(1!3)-O-6-deoxy-a-L-mannopyranosyl-
(1!2)-O-b-D-glucopyranosyl-(1!2)-b-D-glucopyranosyl)oxy]) were isolated as
the alkaline hydrolysis products of the ether-insoluble resin glycosides of the
seeds of crude Cuscuta chinensis (23). The organic portion obtained from the
basic hydrolysis revealed the presence of acetic, propionic, (2S)-methylbutyric, tiglic,
and nilic acids as the esterifying residues of the resin glycoside mixture. All
glycosidic acids have two rhamnose units and one glucose as well as convolvuli-
nolic acid as the aglycone moiety, with the exception of cuscutic acid D, which has
jalapinolic acid. So far, no intact resin glycosides have been isolated with these
glycosidic acids.

Merremoside I

Merremoside I (hexadecanoic acid, (11S)-[(O-6-deoxy-a-L-mannopyranosyl-

(1!4)-O-6-deoxy-a-L-mannopyranosyl-(1!4)-O-6-deoxy-a-L-mannopyranosyl-
(1!4)-6-deoxy-a-L-mannopyranosyl)oxy]) is the glycosidic acid derivative from
basic hydrolysis of the resin glycoside mixtures prepared from fresh tubers of
Merremia mammosa (Lour.) Hallier f. Merremosides A–E (12–16) were isolated
as the major intact diacylated resin glycosides after repeated separation by silica gel
column chromatography and reversed-phase HPLC. L-Rhamnose units are the only
sugar moieties present in the oligosaccharide core, which has jalapinolic acid as the
aglycone. In these macrocyclic compounds, the lactonization site was placed at C-3
of the second rhamnose unit and the oligosaccharide core was esterified by
2-methylpropanoyl and (2S)-methylbutanoyl residues either at C-2 or C-3 of the
third sugar and at C-3 or C-4 of the terminal saccharide unit (24).

Mammoside I (Operculinic Acid C)

Mammoside I (hexadecanoic acid, (11S)-[O-6-deoxy-a-L-mannopyranosyl-(1!4)-

O-6-deoxy-a-L-mannopyranosyl-(1!4)-O-6-deoxy-a-L-mannopyranosyl-(1!2)-
6-deoxy-b-D-galactopyranosyl]oxy) is a linear heterotetrasaccharide of jalapinolic
acid composed by three L-rhamnose units and one D-fucose moiety. This glycosidic
acid was originally isolated by basic hydrolysis of the resin glycosides from
Merremia mammosa (25) and was later named as operculinic acid C after its
isolation from Ipomoea operculata Mart. & Spix. (syn. Operculina macrocarpa
(L.) Urban) (26). The general macrocyclic structures of mammoside A (17) and B
(18) are similar to those of merremosides A (12) and B (13) with the only difference
Resin Glycosides from the Morning Glory Family 89

O
O
O HO OH
O
O O OH
O
R2O OR1
O O
R4O
R3O
OH

Compound R1 R2 R3 R4
12 mba H H mba
13 iba H H iba
14 H mba H iba
15 H iba H iba
16 H iba iba H

being D-fucose instead of L-rhamnose as the initial sugar for the glycosylation
linkage with the aglycone (26).

OH
O
HO O
O

O
O
O OH
O
O
R2O O
O OR1
R4O
HO
OR3

Compound R1 R2 R3 R4
17 mba H H mba
18 iba H H iba
20 dodeca H H dodeca
21 H dodeca H dodeca
22 H deca H mba
24 dodeca H H mba
25 H mba dodeca H
26 H dodeca H mba
30 H deca H H
31 H H H dodeca
90 R. Pereda-Miranda et al.

Ipomoea operculata has afforded three resin glycosides containing this glyco-
sidic acid, operculins VI (19), XI (20), and XII (21). The macrolactone site was
located at C-2 of the first rhamnose unit for 19 while in compounds 20 and 21 the
lactonization was placed at C-3, the same site for mammosides A (17) and B (18).
Two dodecanoyl residues are the fatty acids present in these resin glycosides and
located at C-2 of the second rhamnose and at C-4 of the third rhamnose for operculin
VI (19). For operculins XI (20) and XII (21), they were placed at C-2 or C-3 of the
second rhamnose and C-4 at the third rhamnose (27).

OH
O
HO O
O

O
O

O HO
O
O
R2O OR1 O
O
R4O
HO
OR3

Compound R1 R2 R3 R4
19 dodeca H H dodeca
23 deca H H mba
27 mba H H mba
28 H mba H mba
29 deca H CA deca

The basic hydrolysis of stoloniferins XI (22) and XII (23), isolated from Ipo-
moea stolonifera (Cyrill) J. F. Gmel., afforded operculinic acid C (28). The
lactonization site was placed at C-3 of the second monosaccharide unit for 22,
while for 23 it was placed at C-2. These diacylated resins contain decanoic acid
esterifying position C-3 on the second rhamnose unit for 22 and C-2 for 23. Both
compounds contain (2S)-methylbutyric acid at C-4 on the third rhamnose. Pesca-
preins V (24) and VI (25) are diastereomeric tetraglycosidic lactones of operculinic
acid C, obtained from the hexane-soluble extract of the aerial parts of Ipomoea pes-
caprae (L.) R. Br. Both compounds contain the lactonization site at C-3 of the
second monosaccharide unit and (2S)-methylbutyric and n-dodecanoic acids as
their esterifying residues (29). The methyl ester of operculinic acid C has been
obtained by basic hydrolysis and methylation of the crude resin glycoside mixture
of Ipomoea murucoides Roem. and Schult. (30). Murucoidins XIV–XVI (26–28),
linear diacylated hetero-tetraglycosides, were isolated from the CHCl3-soluble
fraction prepared from flowers by column chromatography over silica gel then
repeated preparative HPLC over reversed-phase C18 silica gel. The lactonization
Resin Glycosides from the Morning Glory Family 91

site by the aglycone was placed at C-3 of the first rhamnose unit for 26, for 27 and
28 at C-2 of the first rhamnose. All these murucoidins contain an esterifying residue
that is composed of dodecanoic or (2S)-methylbutyric acids at the C-2 or C-3
positions on the second rhamnose unit of the oligosaccharide core and a (2S)-
methylbutyric acid at C-4 on the third rhamnose moiety. Operculinic acid C is
also present as the oligosaccharide core of the lipophilic simonin I (29) and
batatinosides II (30) and III (31) from I. batatas (31, 32). These monoacylated
batatinosides were purified by preparative-scale recycling HPLC of the hexane
extract prepared from powdered dry roots. The lactonization site of the aglycone
was placed at C-3 of the first rhamnose unit, except for simonin I (29), where it was
placed at C-2. Batatinoside II (30) has an n-decanoyl residue linked at C-3 of the
third saccharide unit and batatinoside III (31) has a n-dodecanoyl group at C-4 of
the last saccharide unit.

Muricatic Acids A–C

Alkaline hydrolysis of the ether-soluble glycoside fraction obtained from the seeds
of I. muricata (L.) Jacq. provided muricatic acids A–C (33). These muricatic acids
were purified by repeated normal-phase column chromatography. The linear
tetrasaccharide muricatic acid A (hexadecanoic acid, (11S)-[(O-6-deoxy-b-D-
galactopyranosyl-(1!4)-O-6-deoxy-a-L-mannopyranosyl-(1!2)-O-6-deoxy-b-
D-glucopyranosyl-(1!2)-6-deoxy-b-D-glucopyranosyl)oxy] gave one D-fucose,
one L-rhamnose, and two D-quinovose units. Muricatic acid B (hexadecanoic
acid, (11S)-[(O-6-deoxy-b-D-glucopyranosyl-(1!4)-O-6-deoxy-a-L-mannopyra-
nosyl-(1!2)]-O-6-deoxy-b-D-glucopyranosyl-(1!2)-6-deoxy-b-D-glucopyranosyl)‐
oxy]) differs only in the presence of a D-quinovose instead of the terminal fucose.
Muricatic acid C (hexadecanoic acid, (11S)-[(O-6-deoxy-b-D-glucopyranosyl-
(1!3)-O-[6-deoxy-a-L-mannopyranosyl-(1!2)-O-6-deoxy-b-D-glucopyranosyl-
(1!2)-6-deoxy-b-D-glucopyranosyl)oxy] is a branched heterosaccharide and has
one L-rhamnose and three D-quinovose units. For all of these compounds, jalapi-
nolic acid is the aglycone moiety. Muricatic acid A is the oligosaccharide core of
muricatins I–V (32–36) and VII (37). Muricatic acids B and C are the saccharide
cores of muricatins VI (38) and VIII (39), respectively (34, 35).
Muricatic acid C has also been found to be the glycosidic acid core of calonyctin
A, a plant growth regulator isolated from dried leaves of Calonyction aculeatum L.
House (36). It is important to note that calonyctin A has been separated into two
pure components, the homologous glycosides containing the convolvulinolic and
jalapinolic acids as their aglycone moieties, calonyctins A1 (40) and A2 (41). The
lactonization site was placed at C-3 of the second quinovose unit in muricatins
I–VII (32–38), and for muricatin VIII (39) and calonyctins A1 (40) and A2 (41) at
C-2 of the third quinovose unit. The esterifying residues in 32–38 are isobutyric,
(2S)-methylbutyric, and nilic acids (34, 35) while 2-methylbutyric acid is the only
esterifying group in 40 and 41 (36).
92 R. Pereda-Miranda et al.

O
HO O
HO
O
HO O
O O
R4 O
R3 O O
HO O
OH R2O OR1

Compound R1 R2 R3 R4
32 mba H H Omba
33 mba H H Oiba
34 H mba H Omba
35 H mba H Oiba
36 mba H H OH
37 mba H H Onla
38 mba H OH H

O
HO
HO O
O (CH2)nCH3
O HO O
HO O
RO
O
O
O
HO
O HO OH

Compound R1 n
39 H 4
40 mba 4
41 mba 2

Operculinic Acids E and F

Operculinic acids E (hexadecanoic acid, (11S)-[(O-6-deoxy-a-L-mannopyranosyl-

(1!4)-O-6-deoxy-a-L-mannopyranosyl-(1!4)-O-6-deoxy-a-L-mannopyranosyl-
(1!2)-b-D-glucopyranosyl)oxy]) and F (hexadecanoic acid, (11S)-[(O-6-deoxy-a-
L -mannopyranosyl-(1!4)-O-6-deoxy-a- L-mannopyranosyl-(1!4)-O-6-deoxy-
a-L-mannopyranosyl-(1!2)-b-D-xylopyranosyl)oxy]) were obtained by alkaline
hydrolysis of the ether-soluble crude resin glycosides from the roots of Ipomoea
Resin Glycosides from the Morning Glory Family 93

operculata (37). Operculinic acid E has one D-glucose and three L-rhamnose units,
while operculinic acid F has one D-xylose and three L-rhamnoses. In both, the
aglycone moiety is jalapinolic acid. So far, no intact resin glycosides have been
isolated containing operculinic acid F. The methyl ester of operculinic acid E was
obtained by alkaline hydrolysis and methylation of the resin glycoside fraction
prepared from the aerial parts of Ipomoea purpurea (L.) Roth (syn. Pharbitis
purpurea Voigt.). The marubajalapins I–XI (42–52), named after the Japanese
term “maruba-asagao” for this crude drug, were the first examples of resin glyco-
sides based on operculinic acid E, isolated by preparative reversed-phase HPLC.
The lactonization site was placed at C-2 of the first rhamnose, except for maruba-
jalapins V (50), X (51), and XI (52), where it was placed at C-3. n-Octanoyl and
n-decanoyl are the esterifying residues (38, 39).
The methyl ester of operculinic acid E was obtained by basic hydrolysis and
methylation of the crude resin glycoside mixture of I. murucoides. Murucoidins XII
(53) and XIII (54) afford operculinic acid E as their oligosaccharide core. The
lactonization site was placed at C-3 of the first rhamnose unit. These resin glycosides
contain an esterifying residue that is composed of n-dodecanoic or (2S)-methylbu-
tyric acids at the C-2 or C-3 positions on the second rhamnose unit of the oligosac-
charide core and (2S)-methylbutyric acid at C-4 on the third rhamnose (30).

HO
HO O
HO O
O

O
O
HO
O O
O
R2O OR1 O
O
5O
R
R4O
OR3

Compound R1 R2 R3 R4 R5
42 octa H H H octa
43 H octa H H octa
44 octa H H H deca
45 H octa H H deca
46 H deca H H deca
47 octa H octa H octa
48 H octa octa H octa
49 H octa H octa octa
55 dodeca H CA H deca
56 H mba CA H dodeca
57 mba H CA H dodeca
94 R. Pereda-Miranda et al.

The jalapin-like chloroform-soluble material from the dried tubers of I. batatas

was subjected to successive column chromatography over silica gel and HPLC to
yield batatosides J–L (55–57) with the oligosaccharide core based on operculinic
acid E. The lactonization site was placed at C-2 of the first rhamnose unit. Cinnamic
acid was present as the esterifying residue at the C-2 position of the third rhamnose
unit. These resin glycosides also contain esterifying residues composed of n-
dodecanoic or (2S)-methylbutyric acids at the C-2 or C-3 positions on the second
rhamnose unit of the oligosaccharide core as well as n-decanoic or n-dodecanoic
acids at C-4 on the third rhamnose (40).

HO
HO O
HO O
O

O
O
O OH
O
O
R2O O
O OR1
R5O
R4O
OR3

Compound R1 R2 R3 R4 R5
50 H octa H H deca
51 H octa octa H octa
52 octa H H octa octa
53 dodeca H H H mba
54 H dodeca H H mba

Orizabic Acid A

Basic hydrolysis of orizabins I–IV (58–61), isolated by preparative HPLC from the
ether-soluble resins of the root of Ipomoea orizabensis Pelletan, Lebed. ex Steud
afforded orizabic acid A (hexadecanoic acid, (11S)-[(O-6-deoxy-b-D-glucopyrano-
syl-(1!4)-O-6-deoxy-a-L-mannopyranosyl-(1!2)-O-b-D-glucopyranosyl-(1!2)-
6-deoxy-b-D-galactopyranosyl)oxy]) (13). This oligosaccharide afforded one D-qui-
novose, one L-rhamnose, one D-glucose, and one D-fucose unit. Jalapinolic acid is
the aglycone moiety, which is linked to the fucose C-1. The triacylated resin glyco-
sides have (2S)-methylbutanoyl, tigloyl, isobutyl, and niloyl residues as short-chain
esterifying moieties of the oligosaccharide core. The lactonization site were placed
at C-3 of the rhamnose unit. The acylation sites for orizabins I–III (58–60) were
located at C-6 of the glucose unit, C-2 of the third sugar, and C-4 of the quinovose
unit, the terminal monosaccharide. For orizabin IV (61), the esterifying residues
were placed at C-6 of the glucose residue, the second sugar unit, and at C-3 of the
last residue.
Resin Glycosides from the Morning Glory Family 95

Scammonin VII (62), as a minor ether-soluble resin glycoside, was isolated by

reversed-phase HPLC from Convulvulus scammonia L. (41). Under basic hydroly-
sis, it gave orizabic acid A as well as 2-methylbutyric and tiglic acids. Compound
62 exhibits lactonization at C-3 of the rhamnose unit and is acylated by a (2S)-
methylbutanoyl residue at C-2 of the rhamnose unit and a tigloyl residue at C-4 of
the terminal quinovose.

HO

O
HO
R1O O
HO O
O
HO
O
R4O O
O
R3O O
OH O OR2

Compound R1 R2 R3 R4
58 nla tga H mba
59 nla tga H iba
60 nla tga H nla
61 nla tga iba H
62 H mba H tga

Scammonic Acid A

Alkaline hydrolysis of the ether-soluble resin glycosides from the seeds of Con-
vulvulus scammonia produced scammonic acid A (hexadecanoic acid, (11S)-[(O-6-
deoxy-b-D-glucopyranosyl-(1!4)-O-6-deoxy-a-L-mannopyranosyl-(1!2)-O-b-D-
glucopyranosyl-(1!2)-6-deoxy-b-D-glucopyranosyl)oxy]), a major oligosaccharide
formed by jalapinolic acid as the aglycone and two D-quinovoses, one L-rhamnose,
and one D-glucose from the sugar core. The scammonin series of diacetylated
macrocyclic resin glycosides was obtained by column chromatography and HPLC
(42, 43). The lactonization site of the aglycone in scammonins I–VI (63–68) was
placed at C-3 of the third sugar unit. This series results from variations in the type of
esterification by isobutyric, (2S)-methylbutyric, and tiglic acids at C-2 of the
rhamnose and C-4 of the terminal quinovose. Scammonins III–VI (65–68) were
obtained in the form of peracetates because of the great difficulties associated with
their purification as intact products (43).
96 R. Pereda-Miranda et al.

HO O
R1O HO O
R2O O
O
HO
O
R4O O
O
HO O
OH O OR3

Compound R1 R2 R3 R4
63 H H mba tga
64 H H mba H
65 H H iba tga
66 H H tga tga
67 H H iba H
68 H H tga H
69 H H mba nla
70 H mba nla H
71 H nla mba H
72 nla H mba tga
73 H iba nla tga
74 H iba (+)-nla tga
75 H nla iba tga
76 H (+)-nla iba tga
77 H mba nla tga
78 H mba (+)-nla tga
79 H nla mba tga
80 H (+)-nla mba tga
81 H mba nla mba
82 H mba (+)-nla mba
83 H nla mba mba
84 H (+)-nla mba mba
86 H nla nla mba
87 H nla nla tga
88 H nla nla tga
89 H nla ba tga
90 H H nla nla
91 H H ba mba
92 H H nla H
93 H H pa H
96 H nla iba iba
97 H nla mba iba
98 H nla 3-mba mba
99 H nla iba nla
100 H nla 3-mba nla
101 H nla mba nla
102 H H mba iba
103 H H mba mba
Resin Glycosides from the Morning Glory Family 97

Scammonic acid A was also obtained by alkaline hydrolysis of the resin glyco-
side fraction obtained from the Mexican scammony root or false jalap (Ipomoea
orizabensis). The CHCl3-soluble resin glycoside fractions were separated by recy-
cling preparative HPLC using a combination of C18 and aminopropyl silica-based
bonded phases, resulting in the isolation of orizabins V–XXI. The major difference
between each sample was the extent of esterification by (2S)-methylbutyric, tiglic,
and nilic acids. The lactonization site of the aglycone was placed at C-3 of the
L-rhamnose for orizabins V–VII (69–71) and IX–XXI (72–84). Orizabin VIII (85) is
the only member of this series with lactonization at C-3 of the glucose, the second
saccharide unit (44, 45). This series illustrates the application of preparative-scale
recycling HPLC (45) for the complete resolution of diastereomeric mixtures of
niloyl esters involving both the (2R,3R) and (2S,3S) enantiomers of 3-hydroxy-2-
methylbutanoic acid.

HO O
HO
HO O
O O
HO O
O
O
O
O

O O
HO O
HO
OH HO O

O
85

Basic hydrolysis of the resin glycoside fractions obtained from roots of

I. tyrianthina afforded scammonic acid A. However, the botanical name used in
this chemical study for the analyzed plant material was an invalid synonym for
I. orizabensis (46), therefore, as expected, the major components of its lipophilic
fractions, tyrianthins I–VII (86–92), represented only variations in the substitution
pattern of the previously described orizabins (44, 45) since the tyrianthin series was
characterized through esterification as containing butyric, (2S)-methylbutyric, tig-
lic, and nilic acids (47). The polar fractions from this resin glycoside mixture
yielded two macrocyclic resins, the known scammonin VI (68, misreported as the
new tyrianthin VIII) and tyrianthin IX (93), a monosubstituted oligosaccharide
acylated by propionic acid, as well as two acylated derivatives of scammonic acid
A, tyrianthinic acids I (94) and II (95) (48). This type of non-macrocyclic resin
glycoside has only been identified in three other species apart from Mexican
scammony. Two are members of the Convolvulaceae family. The first of these
yielded cuscutic acids A–D, tetrasaccharides isolated from the seeds of Cuscuta
chinensis (20). The second yielded pescaprosides A and B, two pentasaccharides
98 R. Pereda-Miranda et al.

purified from the aerial parts of I. pes-caprae (29, 49). The third example came
from the aerial parts of Scrophularia crypthophila, a species taxonomically unre-
lated to Convolvulaceae and belonging to the Scrophulariaceae, which yielded the
tetrasaccharides, crypthophilic acids A–C (50).

HO O
HO O
HO
HO O
O
HO
O
O
R2O O
HO O
OH HO
OR1
O
OH

Compound R1 R2
94 mba nla
95 mba tga

Another confusion arises in relation to the tetrasaccharides isolated from an ethyl

acetate-soluble fraction of the roots of Ipomoea stans (51–53) since in reality the
analyzed crude drug corresponds to I. orizabensis (10). Three unnamed macrocy-
clic resin glycosides (96–98) and five members of the stancin series (99–103) were
obtained with the same lactonization and substitution pattern observed for the
orizabins (45) with isobutyric, (2S)-methylbutyric, 3-methylbutyric, and nilic
acids as the esterifying residues (51–53). Information was not provided to support
the absolute configuration of the chiral esterifying residues and thus these products
could represent diastereomeric mixtures due to the presence of both enantiomeric
forms of nilic acid (45, 51).

Scammonic Acid B

Scammonin VIII (104), isolated from Convulvulus scammonia, is a linear tetra-

saccharide of jalapinolic acid with two glucoses, one rhamnose, and one quinovose.
This compound represents the only macrocyclic resin glycoside of scammonic acid
B (hexadecanoic acid, (11S)-[(O-b-D-glucopyranosyl-(1!4)-O-6-deoxy-a-L-man-
nopyranosyl-(1!2)-O-b-D-glucopyranosyl-(1!2)-6-deoxy-b-D-glucopyranosyl)oxy]).
Resin Glycosides from the Morning Glory Family 99

The lactonization and acylation by (2S)-methylbutyric acid were placed at C-3 and
C-2 of the third saccharide unit. Tiglic acid was located at C-4 of the terminal
glucose (41).

HO O
HO HO O
HO O
O
HO
O O
HO
O O
O
HO O
OH O O
O
O
104

Soldanellic Acid B

Alkaline hydrolysis of soldanelline B (105), isolated from the chloroform extract of

the roots of Calystegia soldanella (L.) Roem. and Schult. (54), gave soldanellic acid
B (hexadecanoic acid, (11S)-[(O-6-deoxy-a-L-mannopyranosyl-(1!2)-O-[b-D-glu-
copyranosyl-(1!3)]-O-b-D-glucopyranosyl-(1!2)-6-deoxy-b-D-glucopyranosyl)‐
oxy]). This acid is a nonlinear tetrasaccharide composed by one quinovose, two
glucoses, and one rhamnose, and the aglycone moiety is jalapinolic acid. The
lactonization of the natural product was placed at C-2 of the branched glucose
unit while the three acylated substituents were located at C-2 (nilic acid) and C-4
(tiglic acid) of the terminal rhamnose and at C-3 (2S-methylburyric acid) of the
terminal glucose.
HO
HO
HO O
O
HO HO O
O O O
HO O
O
O O O OH
O O
O HO O
O

105
100 R. Pereda-Miranda et al.

Tricoloric Acids A and B

Tricoloric acids A and B were produced by alkaline hydrolysis of the CHCl3-

soluble resin glycosides obtained from aerial parts of Ipomoea tricolor Cav.
(Ipomoea violacea L.) (55, 56). Tricoloric acid A (hexadecanoic acid, (11S)-[(O-
6-deoxy-a-L-mannopyranosyl-(1!3)-O-6-deoxy-a-L-mannopyranosyl-(1!2)-O-
b-D-glucopyranosyl-(1!2)-6-deoxy-b-D-galactopyranosyl)oxy]) has one D-fucose,
one D-glucose, and two L-rhamnose monosaccharide units (55). Tricoloric acid
B (hexadecanoic acid, (11S)-[(O-6-deoxy-a-L-mannopyranosyl-(1!3)-O-6-deoxy-
a-L-mannopyranosyl-(1!2)-O-b-D-glucopyranosyl-(1!2)-6-deoxy-b-D-glucopyra-
nosyl)oxy]) has one D-quinovose, one D-glucose, and two L-rhamnose units.
Jalapinolic acid is the aglycone moiety in these glycoresins. The key to the
successful separation of tricolorin A (106) and its analogues, tricolorins B–E
(107–110), was the use of an amino bonded-phase by HPLC in the recycle mode
(56). The lactonization site of the aglycone was placed at C-3 of the second
saccharide unit in all compounds except tricolorin D (109) at C-6. Tricolorins
B–D (107–109) differ from the general structure of compound 106 in the type of
short-chain acids ester-linked at C-2 and C-4 of the third saccharide unit. These
residues are (2S)-methylbutyric, isobutyric, and nilic acids. The structure of trico-
lorin E (110) was based on tricoloric acid B (56).

R1
R2 O
O
HO
HO
HO O O
O
O O

O
R3O
O
O
O O
HO
HO OH

Compound R1 R2 R3
106 OH H mba
107 OH H iba
108 OH H nla
110 H OH mba
Resin Glycosides from the Morning Glory Family 101

OH
O
O
HO
O O
HO O
O
HO
O
O
O
O O
O
O O
HO
HO
OH
109

Turpethinic Acids A–E

Turpethinic acids A (pentadecanoic acid, 12-[(O-b-D-glucopyranosyl-(1!3)-O-6-

deoxy-a-L-mannopyranosyl-(1!3)-O-b-D-glucopyranosyl-(1!3)-b-D-glucopyra-
nosyl)oxy]-3-hydroxy), B (pentadecanoic acid 12-[(O-b-D-glucopyranosyl-(1!3)-
O-6-deoxy-a-L-mannopyranosyl-(1!3)-O-b-D-glucopyranosyl-(1!3)-b-D-glucopyra-
nosyl)oxy]-4-hydroxy), C (hexadecanoic acid, 12-[(O-b-D-glucopyranosyl-(1!3)-
O-6-deoxy-a-L-mannopyranosyl-(1!3)-O-b-D-glucopyranosyl-(1!3)-b-D-gluco-
pyranosyl)oxy]-4-hydroxy), D (hexadecanoic acid, 12-[(O-b-D-glucopyranosyl-
(1!3)-O-6-deoxy-a-L-mannopyranosyl-(1!3)-O-b-D-glucopyranosyl-(1!3)-b-D-
glucopyranosyl)oxy]-3-hydroxy), and E (hexadecanoic acid, 11-[(O-b-D-gluco-
pyranosyl-(1!3)-O-6-deoxy-a-L-mannopyranosyl-(1!3)-O-b-D-glucopyranosyl-
(1!3)-b-D-glucopyranosyl)oxy]) were obtained by alkaline hydrolysis of the
ethanol-soluble resin glycosides of Ipomoea turphetum (L.) R. Br. (57). These
glycosidic acids are composed of one rhamnose and three glucose units with 3,12-
dihydroxypentadecanoic, 4,12-dihydroxypentadecanoic, 4,12-dihydroxyhexade-
canoic, 3,12-dihydroxyhexadecanoic, and 11-hydroxyhexadecanoic acids, as
their aglycones.

3.2.4. Pentasaccharides

Arboresinic Acid

The CHCl3 extracts from roots of Ipomoea arborescens Humb. and Bonpl. were
fractionated by column chromatography on silica gel. The alkaline hydrolysis of
102 R. Pereda-Miranda et al.

the less polar fractions produced arboresinic acid (hexadecanoic acid, (11S)-[(O-
6-deoxy-a-L-mannopyranosyl-(1!4)-O-[b-D-glucopyranosyl-(1!2)]-O-6-deoxy-a-
L-mannopyranosyl-(1!4)-O-6-deoxy-a-L-mannopyranosyl-(1!2)-b-D-glucopyra-
nosyl)oxy]) with a linear oligosaccharide core of two D-glucoses and three
L-rhamnoses, as well as jalapinolic acid as the aglycone moiety. Six intact acylated
resin glycosides derived from this glycosidic acid were isolated by HPLC and
named arboresins I–VI (111–116). For all, the lactonization site was placed at
C-2 of the second sugar unit, a n-dodecanoyl group at C-2 of the third sugar, and
a niloyl residue at C-3 of the fourth sugar. The presence of congeners in this species
is a consequence of variations in the type of acylating groups at C-4 of the fourth
saccharide, i.e., acetic, propionic, butanoic, (2S)-methylbutanoic, or tiglic acids
(58).

HO
HO O
HO O
O

O
O
HO
O O
O
O
HO
O O
RO
O O
O
O
OH O OH

OH
HO
OH

Compound R
111 H
112 ac
113 pa
114 ba
115 mba
116 tga

Dichroside D

The EtOH extract of Ipomoea dichroa Choisy was fractionated into different organic
solvents. The n-hexane-soluble fraction was resolved by column chromatography to
afford dichrosides A–D. The major component dichroside D (hexadecanoic acid,
(11S)-[(O-6-deoxy-a-L-mannopyranosyl-(1!3)-O-[b-D-glucopyranosyl-(1!4)]-
O-6-deoxy-a-L-mannopyranosyl-(1!4)-O-6-deoxy-a-L-mannopyranosyl-(1!2)-
6-deoxy-a-L-mannopyranosyl)oxy]) was subjected to catalytic hydrogenation.
Resin Glycosides from the Morning Glory Family 103

Its chemical structure, characterized by degradative chemical procedures in con-

junction with spectroscopic and spectrometric techniques, corresponded to a pen-
tasaccharide of jalapinolic acid with one unit of D-glucose and four L-rhamnoses.
The structures of the intact dichrosides A–D remain unsolved (59).

Merremoside J

Merremoside J (hexadecanoic acid, (11S)-[(O-6-deoxy-a-L-mannopyranosyl-

(1!4)-O-[b-D-glucopyranosyl-(1!3)]-O-6-deoxy-a-L-mannopyranosyl-(1!4)-
O-6-deoxy-a-L-mannopyranosyl-(1!4)-6-deoxy-a-L-mannopyranosyl)oxy]), one
of the alkaline hydrolysis products from the resin glycoside mixture of Ipomoea
mammosa (Lour.) Hallier f. (syn. Merremia mammosa (Lour.) Hallier), is a
branched pentasaccharide of jalapinolic acid with one D-glucose and four
L-rhamnoses. The methanol extract obtained from the crude drug gave four resin
glycosides, merremosides f, g, h1, and h2 (117–120). The lactonization site of the
aglycone was placed at C-3 of the second saccharide unit in merremosides f and g
and at C-2 of the same sugar residue in merremosides h1 and h2. Differences in the
acylation pattern at C-2 of the third rhamnose as well as at C-4 of the terminal
rhamnose are responsible for the chemical diversity in the merremoside series with
isobutyric and (2S)-methylbutyric acids at these two positions (60).

O
O
HO
O HO
O
O
O HO
O
O
O
O OR
O
HO O OH
O OH

OH
HO
OH

Compound R
117 iba
118 mba
104 R. Pereda-Miranda et al.

O
O
HO
O HO
O
HO
O O
O
O O
O OR
O
HO O OH
O OH

OH
HO
OH

Compound R
119 mba
120 iba

Microphyllic Acid

The alkaline hydrolysis of resins from Convolvulus microphyllus Sieb. ex Spreng.

yielded microphyllic acid (hexadecanoic acid, (11S)-[(O-6-deoxy-a-L-mannopyra-
nosyl-(1!4)-O-[6-deoxy-a-L-mannopyranosyl-(1!6)]-O-b-D-glucopyranosyl-
(1!3)-O-6-deoxy-a-L-mannopyranosyl-(1!3)-6-deoxy-b-D-galactopyranosyl)oxy]),
a nonlinear oligosaccharide with three L-rhamnose, one D-fucose, and one D-glucose
units, as well as jalapinolic acid. Derivatization was used to elucidate its structure
by application of GC-MS (61).

Multifidinic Acids A and B

Ipomoea multifida Cardinal Climber (syn. Quamoclit multifida Raf.) is an ornamen-

tal hybrid of Quamoclit pinnata and Q. coccinea. Alkaline hydrolysis of the ether-
soluble resin glycosides obtained from seeds gave multifidinic acids A (tetradeca-
noic acid, (11S)-[(O-6-deoxy-a-L-mannopyranosyl-(1!4)-O-[b-D-glucopyranosyl-
(1!3)]-O-6-deoxy-a-L-mannopyranosyl-(1!4)-O-6-deoxy-a-L-mannopyranosyl-
Resin Glycosides from the Morning Glory Family 105

(1!2)-6-deoxy-b-D-glucopyranosyl)oxy]) and B (hexadecanoic acid, (11S)-[(O-6-

deoxy-a-L-mannopyranosyl-(1!4)]-O-[b-D-glucopyranosyl-(1!3)]-O-6-deoxy-
a-L-mannopyranosyl-(1!4)-O-6-deoxy-a-L-mannopyranosyl-(1!2)-6-deoxy-b-D-
glucopyranosyl)oxy]). The sugar core of both is similar except for the aglycone
moiety, convolvulinolic acid for A and jalapinolic acid for B. The nonlinear oligo-
saccharide has one D-glucose, one D-quinovose, and three L-rhamnose units. Two
intact acylated resin glycosides derived from A were isolated and named multifidins
I (121) and II (122). The lactonization site of the aglycone was placed at C-2 of the
second saccharide unit and a (2S)-methylbutyric acid was located at C-4 of the
fourth unit. Variations in the length of the acylating fatty acids at C-2 of the second
rhamnose were observed, with n-decanoic acid as the esterifying residue in 121 and
n-dodecanoic acid in 122 (62).

HO O
HO O
O

O
O
HO
O O
O
O
O
O OR
O
HO O OH
O OH

OH
HO
OH

Compound R
121 deca
122 dodeca

Murucinic Acid

The roots of the misidentified plant material Ipomoea murucoides were dried,
pulverized, and macerated in chloroform. In reality, the analyzed plant material
was I. arborescens as revealed by its chemistry which proved to be totally different
from that identified for I. murucoides (63), when the latter was fractionated by
column chromatography. The basic hydrolysis of the resinous chromatographic
fractions of this sample produced the same glycosidic acid derivative ultimately
found in I. arborescens, i.e., murucinic acid (hexadecanoic acid, (11S)-[(O-b-D-
106 R. Pereda-Miranda et al.

glucopyranosyl-(1!2)-O-6-deoxy-a-L-mannopyranosyl-(1!4)-O-6-deoxy-a-L-
mannopyranosyl-(1!4)-O-6-deoxy-a-L-mannopyranosyl-(1!2)-O-6-deoxy-b-D-
glucopyranosyl)oxy]) (58). Nine intact acylated resin glycosides, murucins I–IX
(123–131), derived from this glycosidic acid have been isolated and characterized.
For all murucins the lactonization site of the aglycone was placed at C-2 of the
second saccharide unit, and n-dodecanoic acid as the esterifying group at C-2 of the
third saccharide unit. The presence of congeners in the murucin series is a conse-
quence of the variations in the type of acylating groups at C-3 and C-4 of the fourth
saccharide unit; a niloyl residue could be an esterifying group at C-3. Acetyl,
propanoyl, butanoyl, (2S)-methylbutanoyl, 3-hydroxy-2-methylbutanoyl, or tigloyl
residues could be the esterifying group at C-4 (63).

HO O
HO O
O

O
O
HO
O O
O
O
HO
O O
R2O
R1O O
O

O OH

OH
HO
OH

Compound R1 R2
123 H ac
124 H pa
125 H ba
126 H mba
127 H nla
128 nla ac
129 nla ba
130 nla tga
131 H H
Resin Glycosides from the Morning Glory Family 107

R2
R3
R1 O
HO O
O

O
O
HO
O O
O
O
O
9
O OR4
R O
O OH
R8 O
OR7

R6O
HO
OR5
Compound R1 R2 R3 R4 R5 R6 R7 R8 R9
132 H OH CH3 deca H H H H H
133 H OH CH3 mba H H H CA dodeca
134 H OH CH3 mba H H CA H dodeca
135 H OH CH3 mba H H H CA mba
136 H OH CH3 mba H H H CA octa
137 H OH CH3 Octa H H H CA octa
138 H OH CH3 dodeca H H H CA (-)-(2R)-mba
139 H OH CH3 dodeca H H H CA mba
140 H OH CH3 dodeca H H H mba CA
141 H OH CH3 dodeca H H H CA octa
142 H OH CH3 dodeca H H CA H propa
143 H OH CH3 dodeca H H H H propa
144 H OH CH3 dodeca H H H H dodeca
145 H OH CH3 deca H H H H deca
146 OH H CH2OH dodeca H H H H dodeca
147 OH H CH2OH deca H H H H deca
149 H OH CH3 dodeca H H H H deca
150 H OH CH3 deca H H H H dodeca
151 OH H CH2OH dodeca H H H H deca
152 OH H CH2OH deca H H H H dodeca
153 OH H CH2OH dodeca H H H H H
154 OH H CH2OH deca H H H H H
155 OH H CH2OH H H H H H dodeca
156 H OH CH3 deca H H H H mba
157 H OH CH3 deca H H H H mba
158 H OH CH3 deca H H H H hexa
159 H OH CH3 deca H H H H hexa
160 H OH CH3 mba H H H H iba
161 H OH CH3 iba H H H H iba
162 H OH CH3 mba H H H H mba
165 H OH CH3 dodeca H H H H mba
166 H OH CH3 hexadeca H hexadeca H H hexadeca
167 H OH CH3 hexadeca hexadeca H H H hexadeca
168 H OH CH3 hexadeca H hexadeca H H hexadeca
169 H OH CH3 hexadeca octadeca H H H hexadeca
170 H OH CH3 hexadeca octadeca H H H hexadeca
171 H OH CH3 hexadeca H octadeca H H hexadeca
172 H OH CH3 hexadeca eicosa H H H hexadeca
173 H OH CH3 hexadeca H eicosa H H hexadeca
174 H OH CH3 hexadeca H H H H hexadeca
175 H OH CH3 hexadeca H H H H hexadeca
176 H OH CH3 dodeca H H H H tga
108 R. Pereda-Miranda et al.

OH
O
HO O
O

O
O
O
O OH
O
O
O
O OR1
R2O
HO O OH
OH

HO
HO
OH

Compound R1 R2
148 dodeca dodeca
163 mba mba
164 dodeca mba

Operculinic Acids A, B, D, and G

Alkaline hydrolysis of the ether-soluble resin glycosides from Brazilian jalap, the
roots of Ipomoea operculata (Gomes) Mart., gave four pentasaccharides of jalapi-
nolic acid, named operculinic acids A (hexadecanoic acid, (11S)-[(O-6-deoxy-a-L-
mannopyranosyl-(1!4)]-O-[b-D-glucopyranosyl-(1!3)]-O-6-deoxy-a-L-manno-
pyranosyl-(1!4)-O-6-deoxy-a-L-mannopyranosyl-(1!2)-6-deoxy-b-D-galacto-
pyranosyl)oxy]), B (hexadecanoic acid, (11S)-[(O-6-deoxy-a-L-mannopyranosyl-
(1!4)-O-[b-D-glucopyranosyl-(1!3)]-O-6-deoxy-a-L-mannopyranosyl-(1!4)-
O-6-deoxy-a-L-mannopyranosyl-(1!2)-b-D-glucopyranosyl)oxy]), D (hexadeca-
noic acid, (11S)-[(O-6-deoxy-a-L-mannopyranosyl-(1!4)-O-[b-D-glucopyrano-
syl-(1!3)]-O-6-deoxy-a-L-mannopyranosyl-(1!4)-O-6-deoxy-a-L-mannopyrano-
syl-(1!2)-b-D-xylopyranosyl)oxy]), and G (hexadecanoic acid, (11S)-[(O-6-
deoxy-a-L-mannopyranosyl-(1!4)-O-[2-O-methyl-b-D-glucopyranosyl-(1!3)]-
O-6-deoxy-a-L-mannopyranosyl-(1!4)-O-6-deoxy-a-L-mannopyranosyl-(1!2)-
6-deoxy-b-D-galactopyranosyl)oxy]) (26). Their structures are similar, only differ-
ing in the first monosaccharide unit: for acid A this is D-fucose, for acid B, D-glu-
cose, and for acid D, D-xylose. The general structure of operculinic acid G is similar
to that elucidated for operculinic acid A, differing only in the methylation of the
hydroxy group at position C-2 of the terminal monosaccharide unit. Thus, this
glycosidic acid seems to represent an artifact of solvent extraction.
Resin Glycosides from the Morning Glory Family 109

Thirty-eight intact acylated resin glycosides derived from operculinic acid A

have been isolated: batatinoside VI (132), batatoside H (133) and batatoside I (134)
from I. batatas (L.) Lam. (40, 64), intrapilosins I–VII (135–141) from I. intrapilosa
Rose (65), leptophyllins A (142) and B (143) from I. leptophylla Torr. (66),
operculins I (144), II (145), V (148), VII (149), and VIII (150) from I. operculata
(Gomes) Mart. (67, 68), stoloniferins IV–VII (156–159) from I. stolonifera (Cyrill.)
J. F. Gmel. (69), mammosides H1 (160) and H2 (161) from I. mammosa Choisy
(syn. Merremia mammosa (Lour.) Hall. f.) (25), murucoidins IV (162), V (163),
and XI (164) from I. murucoides (Roem and Schult) (70, 71), quamoclin IV (165)
from I. quamoclit L. (syn. Quamoclit pennata Bojer) (72), tuguajalapins I–X (166–
175) from M. hungaiensis Lingelish and Borza (73), and digitatajalapin I (176)
from I. digitata L. (74). Seven intact acylated resin glycosides derived from
operculinic acid B have also been isolated, namely, operculins III (146), IV
(147), IX (151), X (152), XVI (153), XVII (154), and XVIII (155). The lactoniza-
tion site of the aglycone was placed at C-2 of the second saccharide unit in all
compounds except for operculin V (148) and murucoidins V (163) and XI (164),
where it was placed at C-3. Different types of acylating groups at C-2 of the third
saccharide unit, and at C-2, C-3, and/or C-4 of the fourth saccharide, contribute to
the chemical diversity of these pentasaccharides.

Pescaprosides A, B, C, and E

The n-hexane-soluble extract from the aerial parts of the Mexican herbal drug
“riñonina”, Ipomoea pes-caprae var. brasiliensis (L.) Oost., the “beach morning
glory” when separated using preparative-scale recycling HPLC, yielded two lipo-
philic glycosides, pescaprosides A (177) and B (178). The structure of pescaproside
A (hexadecanoic acid, (11S)-[[O-6-deoxy-a-L-mannopyranosyl-(1!3)-O-[6-
deoxy-a-L-mannopyranosyl-(1!4)]-O-6-deoxy-2-O-(1-oxododecyl)-a-L-manno-
pyranosyl-(1!4)-O-6-deoxy-a-L-mannopyranosyl-(1!2)-6-deoxy-b-D-galacto-
pyranosyl)oxy]-methyl ester) is similar to that of pescaproside B (hexadecanoic
acid, (11S)-[[(O-6-deoxy-a-L-mannopyranosyl-(1!3)-O-[6-deoxy-4-O-[(2S)-2-
methyl-1-oxobutyl]-a-L-mannopyranosyl-(1!4)]-O-6-deoxy-2-O-dodecyl-a-L-
mannopyranosyl-(1!4)-O-6-deoxy-a-L-mannopyranosyl-(1!2)-6-deoxy-b-D-
galactopyranosyl]oxy]-methyl ester), with the only variation being the substitution
by a (2S)-methylbutyric acid residue at position C-4 of the terminal rhamnose unit
in pescaproside B (29, 49). The structure of pescaproside C is similar to that of
simonic acids A and B with the only difference being the presence of D-xylopyra-
nose as the first monosaccharide in the oligosaccharide core. The four remaining
sugars in this nonlinear glycosidic acid were identified as L-rhamnose (75).
Pescaprein XVIII (179) was isolated from the lipophilic fractions of the beach
morning glory and its oligosaccharide core was characterized as pescaproside C
(hexadecanoic acid, (11S)-[[O-6-deoxy-a-L-mannopyranosyl-(1!3)-O-[6-deoxy-
a-L-mannopyranosyl-(1!4)]-O-6-deoxy-a-L-mannopyranosyl-(1!4)-O-6-deoxy-
a-L-mannopyranosyl-(1!3)-b-D-xylopyranosyl]oxy]). The lactonization site of the
110 R. Pereda-Miranda et al.

OH
O
HO O
O

O
O
HO
O HO
O

O O
O
RO
HO O
OH O
O
OH O
OH
HO

Compound R
177 H
178 mba

aglycone was placed at C-3 of the second saccharide unit. An n-dodecanoyl group
was located at C-2 of the third saccharide and a (2S)-methylbutanoyl residue at
C-4 of the fourth sugar (75). The structure of pescaproside E (hexadecanoic acid,
(11S)-[[O-6-deoxy-a-L-mannopyranosyl-(1!3)-O-[6-deoxy-a-L-mannopyrano-
syl-(1!4)]-O-6-deoxy-a-L-mannopyranosyl-(1!4)-O-6-deoxy-b-D-galactopyra-
nosyl-(1!2)-6-deoxy-a-L-mannopyranosyl]oxy]) was proposed for the major
saponification product of a mixture of resin glycosides isolated from a collection
of beach morning glories from India. However, the glycosidation sequence, which
was mainly characterized by the use of chemical degradations, seems to be not
properly deduced (76). The D-Fuc-(1!2)-L-Rha disaccharide subunit, proposed
instead of the highly preserved L-Rha-(1!2)-D-Fuc moiety, has not been reported
in any other resin glycoside.

Pharbitic Acid C

The alkaline hydrolysis of the ether-insoluble resin glycoside fraction from seeds of
Ipomoea nil (L.) Roth (syn. Pharbitis nil Choisy) yielded a pentasaccharide of
ipurolic acid, which was named pharbitic acid C (tetradecanoic acid, 11-[(O-6-
deoxy-b-D-glucopyranosyl-(1!4)-O-6-deoxy-a-L-mannopyranosyl-(1!6)-O-[6-
deoxy-a-L-mannopyranosyl-(1!2)-O-b-D-glucopyranosyl-(1!2)]-b-D-glucopyra-
nosyl)oxy]-3-hydroxy). On complete hydrolysis, it produced two D-glucoses, two
L-rhamnoses, one D-quinovose, and the aglycone moiety (77).
Resin Glycosides from the Morning Glory Family 111

OH
O
O O
HO
O
O
O
O OH
O
O O
O
O O

O HO O O
OH
OH
OH
HO
179

Quamoclinic Acid A

The MeOH extracts from seeds of Ipomoea quamoclit L. (syn. Quamoclit pennata
Bojer) were partitioned between diethyl ether and H2O. The alkaline hydrolysis of
the ether-soluble fraction gave quamoclinic acid A (tetradecanoic acid, (11S)-[(O-
6-deoxy-a-L-mannopyranosyl-(1!4)-O-[b-D-glucopyranosyl-(1!3)]-O-6-deoxy-
a-L-mannopyranosyl-(1!4)-O-6-deoxy-a-L-mannopyranosyl-(1!2)-6-deoxy-b-
D-galactopyranosyl)oxy], the structure of which is similar to that of operculinic
acid A, with the only difference being in the aglycone moiety, namely, convol-
vulinolic acid for quamoclinic acid A and jalapinolic acid for operculinic acid A.
Three intact acylated resin glycosides were isolated and elucidated structurally,
quamoclins I–III (180–182). The lactonization site of the aglycone was placed at
C-2 of the second saccharide unit in compounds 180 and 182, while in 181 it was
placed at C-3. In all quamoclins, a (2S)-methylbutanoyl group was located at C-4
of the fourth saccharide unit (72). These were the first examples described of
ether-soluble resin glycosides in which methylbutyric acid coexists with long-
chain fatty acids such as n-decanoic or n-dodecanoic acids at C-2 of the third
saccharide unit.

Simonic Acids A and B

Alkaline hydrolysis of the CHCl3-soluble resin glycoside mixture from dry roots of
sweet potato (Ipomoea batatas) afforded two glycosidic acids, simonic acids A
(hexadecanoic acid, (11S)-[(O-6-deoxy-a-L-mannopyranosyl-(1!3)-O-[6-deoxy-
a-L-mannopyranosyl-(1!4)]-O-6-deoxy-a-L-mannopyranosyl-(1!4)-O-6-deoxy-
112 R. Pereda-Miranda et al.

OH
O
HO O
O

O
O
HO
O O
O
O
O
O OR
O
HO O
O OH OH

OH
HO
HO

Compound R
180 dodeca
182 deca

OH
O
HO O
O

O
O
O
O OH
O
O
O
O O
O
HO O O
O OH OH

OH
HO
HO
181

a-L-mannopyranosyl-(1!2)-b-D-glucopyranosyl)oxy]) and B (hexadecanoic acid,

(11S)-[(O-6-deoxy-a-L-mannopyranosyl-(1!3)-O-[6-deoxy-a-L-mannopyrano-
syl-(1!4)]-O-6-deoxy-a-L-mannopyranosyl-(1!4)-O-6-deoxy-a-L-mannopyra-
nosyl-(1!2)-6-deoxy-b-D-galactopyranosyl)oxy]) (31). The structures of these
compounds are similar, with the difference being the presence of D-glucopyra-
nose as the first monosaccharide of the sugar chain for simonic acid A and
Resin Glycosides from the Morning Glory Family 113

D-fucopyranoside for simonic acid B. The other four monosaccharide units in the
nonlinear oligosaccharide core were identified as L-rhamnoses, and their aglycone
moiety was jalapinolic acid.

R2
R3
R1 O
HO O
O

O
O
O OH
O
O
O O
O OR4
R7O
R 6O O
OR5 OH
OH
HO

Compound R1 R2 R3 R4 R5 R6 R7
183 OH H CH2OH mba H H dodeca
184 H OH CH3 mba H H dodeca
185 H OH CH3 dodeca H H dodeca
186 H OH CH3 octa H H dodeca
187 H OH CH3 mba H CA dodeca
188 H OH CH3 mba H H dodeca
190 H OH CH3 mba CA iba H
191 H OH CH3 ba H CA iba
192 H OH CH3 mba CA dodeca H
204 OH H CH2OH dodeca H H mba
207 H OH CH3 mba H H iba
208 H OH CH3 (8R)-hydroxy-dodeca H H mba
209 H OH CH3 dodeca H H H
210 H OH CH3 dodeca H H iba
211 H OH CH3 dodeca H H mba
212 H OH CH3 deca H H hexa
213 H OH CH3 deca H H H
214 H OH CH3 iba H H dodeca
215 H OH CH3 deca H H hexa
216 H OH CH3 deca H CA mba
217 H OH CH3 deca CA H mba
218 H OH CH3 deca H CA iba
219 H OH CH3 deca CA H iba
220 H OH CH3 dodeca H CA iba
221 H OH CH3 dodeca CA H iba
222 H OH CH3 dodeca H CA mba
223 H OH CH3 dodeca CA H mba
224 H OH CH3 mba H H mba
225 H OH CH3 deca H H iba
226 H OH CH3 deca H H mba

Six intact acylated resin glycosides containing simonic acid A have been iso-
lated: simonin II (183), batatosides M (197) and N (198) from I. batatas (31, 40)
114 R. Pereda-Miranda et al.

and murucoidins VI–VIII (204–206) from I. murucoides (71). Simonic acid B has
been found to be the glycosidic acid core in the following resin glycosides:
simonins III–V (184–186), batatinosides I (187), IV (188) and V (189), and batato-
sides A–G (190–196) and O–P (199–200) from I. batatas (40, 64, 78, 79), muru-
coidins I–III (201–203), IX (207) and X (208) from I. murucoides (70, 71), and
pescapreins I–IV (209–212), VII–IX (213–215) and X–XVII (216–223) from I. pes-
caprae (29, 49, 80), and stoloniferins I–III (224–226) from I. stolonifera (69). The
lactonization site of the aglycone was placed at C-3 of the second saccharide unit in
all these compounds except for batatinoside V (189), batatosides D–G (193–196)
and M–P (197–200), and murucoidins I–III (201–203) and VII–VIII (205–206),
where it was placed at C-2. The presence of congeners in these series is a conse-
quence of the variations in the type of acylating groups at C-2 of the third
saccharide unit, and at C-2, C-3 and C-4 of the fourth saccharide unit. It has been
reported that this diastereomerism at positions C-2 and C-3 could be a result of a
transesterification via an ortho-acid ester intermediate that can take place in slightly
acidic or neutral aqueous solution (80).

R2
R3
R1 O
HO O
O

O
O
HO
O O
O
O
O OR4
O
R7O
R6O OR5 O
OH
OH
HO

Compound R1 R2 R3 R4 R5 R6 R7
189 H OH CH3 deca H H H
193 H OH CH3 mba H CA dodeca
194 H OH CH3 mba CA H dodeca
195 H OH CH3 mba CA dodeca H
196 H OH CH3 dodeca H CA ba
197 OH H CH2OH dodeca CA H mba
198 OH H CH2OH mba H CA iba
199 H OH CH3 iba CA H dode
200 H OH CH3 deca CA H iba
201 H OH CH3 mba H H H
202 H OH CH3 mba H H iba
203 H OH CH3 mba H H mba
205 OH H CH2OH mba H H iba
206 OH H CH2OH mba H H mba
Resin Glycosides from the Morning Glory Family 115

Soldanellic Acid A

From the chloroform-soluble extract obtained from the lyophilized root of Calystegia
soldanella, an intact acylated resin glycoside, soldanelline A (227), was isolated (81).
Its nonlinear pentasaccharide core has one D-quinovose, three D-glucoses, and one
L-rhamnose, and as glycosidic acid, soldanellic acid. A (hexadecanoic acid, (11S)-
[(O-b-D-glucopyranosyl-(1!3)-O-6-deoxy-a-L-mannopyranosyl-(1!2)-O-[b-D-
glucopyranosyl-(1!3)]-O-b-D-glucopyranosyl-(1!2)-6-deoxy-b-D-glucopyranosyl)
oxy]). The aglycone moiety is jalapinolic acid and the lactonization site of the
aglycone was placed at C-2 of the second glucose unit, which represents the terminal
and branched sugar for this pentasaccharide. Three sites of acylation were identified:
nilic and tiglic acids at C-2 and C-4 of the third sugar (rhamnose), and (2S)-
methylbutyric acid at C-3 of the branched glucose.

O O O
O HO O
HO O HO
OH
OH O O
O HO
O
O O
O
O
OH
HO O O O
HO
OH O OH
227

Woodrosinic Acid A

Two ether-insoluble resin glycosides named woodrosins I (228) and II (229) were
isolated from the stems of Ipomoea tuberosa L. (syn. Merremia tuberosa (L.)
Rendle) (82). Their oligosaccharide core was identified as a branched hetero-
pentasaccharide, woodrosinic acid A (hexadecanoic acid, (11S)-[(O-6-deoxy-a-
L-mannopyranosyl-(1!2)-O-[b-D-glucopyranosyl-(1!6)-b-D-glucopyranosyl-(1!3)]-
O-b-D-glucopyranosyl-(1!2)-b-D-glucopyranosyl)oxy]), composed by four D-
glucoses and one L-rhamnose. Jalapinolic acid is the aglycone. For 228 and 229,
the lactonization site was placed at C-2 of the fourth D-glucose unit. The branched
monosaccharide represents the desoxyhexose unit diacylated by (2S)-methylbu-
tyric acid at C-2 and C-4. The type of acylating groups at C-3 of the third
saccharide unit leads to the structural difference between natural products 228
and 229.
116 R. Pereda-Miranda et al.

HO
HO
HO
HO O
HO O
HO O
O O OH
O O
HO
O O O
O O
RO OH
O O
O
HO O
O
O

Compound R
228 mba
229 iba

3.2.5. Hexasaccharides

Lonchophyllic Acid

Alkaline hydrolysis of the methanol-soluble resin glycosides from Ipomoea lon-

chopylla J. Black afforded a nonlinear hetero-hexasaccharide of ipurolic acid with
two D-glucoses, one D-fucose, two D-quinovoses, and one L-rhamnose (tetradeca-
noic acid, (11S)-[(O-6-deoxy-b-D-glucopyranosyl-(1!2)-O-b-D-glucopyranosyl-
(1!3)-O-[6-deoxy-a-L-mannopyranosyl-(1!4)]-O-6-deoxy-b-D-glucopyranosyl-
(1!2)-O-b-D-glucopyranosyl-(1!2)-6-deoxy-b-D-galactopyranosyl)oxy]-(3S)-
hydroxy) (83).

Operculinic Acid

Saponification of the diethyl ether-insoluble resin glycosides from Ipomoea oper-

culata (Gomes) Martins, produced a glucorhamnohexasaccharide of 3,12-dihy-
droxypalmitic acid, operculinic acid (hexadecanoic acid, 12S-([O-6-deoxy-a-L-
mannopyranosyl-(1!6)-O-[a-D-glucopyranosyl-(1!4)]-O-a-D-glucopyranosyl-
(1!3)-O-6-deoxy-a-L-mannopyranosyl-(1!2)-O-[b-D-glucopyranosyl-(1!3)]-
b-D-glucopyranosyl]oxy)-3-hydroxy) (84). This nonlinear glycosidic acid has four
D-glucoses and two L-rhamnoses.
Resin Glycosides from the Morning Glory Family 117

Pharbitic Acids B and D

Two glycosidic acids, pharbitic acids B and D, were isolated from alkaline hydro-
lysis of the ether-insoluble resin glycosides of Ipomoea nil (L.) Roth (syn. Pharbitis
nil Choisy) seeds. Complete hydrolysis gave two D-glucoses, three L-rhamnoses,
and one D-quinovose, with the only difference being found in the aglycone moiety,
3,11-dihydroxyhexadecanoic acid for pharbitic acid B (hexadecanoic acid, (11S)-
[(O-6-deoxy-a-L-mannopyranosyl-(1!3)-O-6-deoxy-b-D-glucopyranosyl-(1!4)-
O-6-deoxy-a-L-mannopyranosyl-(1!6)-O-[6-deoxy-a-L-mannopyranosyl-(1!2)-
O-b-D-glucopyranosyl-(1!2)]-b-D-glucopyranosyl)oxy]-3-hydroxy) and ipurolic
acid for pharbitic acid D (tetradecanoic acid, (11S)-[(O-6-deoxy-a-L-mannopyra-
nosyl-(1!3)-O-6-deoxy-b-D-glucopyranosyl-(1!4)-O-6-deoxy-a-L-mannopyra-
nosyl-(1!6)-O-[6-deoxy-a- L-mannopyranosyl-(1!2)-O-b-D -glucopyranosyl-
(1!2)]-b-D-glucopyranosyl)oxy]-(3S)-hydroxy) (85, 86).

Purgic Acids A and B

The authentic jalap root [Ipomoea purga (Wender) Hayne] MeOH-soluble resin
glycosides have been found to be composed by two nonlinear hetero-hexasaccha-
rides of convolvulinolic and jalapinolic acids, purgic acids A (tetradecanoic acid,
(11S)-[(O-6-deoxy-b-D-glucopyranosyl-(1!2)-O-b-D-glucopyranosyl-(1!3)-O-
[6-deoxy-b-D-galactopyranosyl-(1!4)]-O-6-deoxy-a-L-mannopyranosyl-(1!2)-
O-b-D-glucopyranosyl-(1!2)-6-deoxy-b-D-glucopyranosyl)oxy]) and B (hexade-
canoic acid, (11S)-[(O-6-deoxy-b-D-glucopyranosyl-(1!2)-O-b-D-glucopyrano-
syl-(1!3)-O-[6-deoxy-b-D-galactopyranosyl-(1!4)]-O-6-deoxy-a-L-mannopy-
ranosyl-(1!2)-O-b-D-glucopyranosyl-(1!2)-6-deoxy-b-D-glucopyranosyl)oxy])
(10). The oligosaccharide core has two D-glucoses, two D-quinovoses, one D-fucose,
and one L-rhamnose.

3.2.6. Ester-Type Oligomers

Batatins I and II

Batatins I (230) and II (231), two intact ester-type dimers of acylated pentasacchari-
des, were isolated by recycling HPLC from the n-hexane-soluble extract of the
white-fleshed, and white-skinned staple-type cultivar of sweet potato (Ipomoea
batatas). The glycosidic acid forming each branched pentasaccharide monomeric
unit was confirmed as simonic acid B through saponification of pure 230 and 231.
The oligosaccharide core was esterified by three different fatty acids at the same
positions on C-2 of the second rhamnose unit, as well as C-2 (or C-3) and C-4 of the
third rhamnose moiety. The acylating residues were identified as (+)-(2S)-methyl-
butanoic, n-dodecanoic, and cinnamic acids. The site of lactonization by the aglycone
in the macrocyclic unit was placed at C-3 of the second saccharide. The position for
118 R. Pereda-Miranda et al.

the ester linkage for the noncyclic monomeric unit on the macrocyclic pentasac-
charide was identified as C-3 of the terminal rhamnose (78). Both 230 and 231
represent dimers of batatinoside I (187).

OH
O
HO O
O

O
O
O
O HO
O
O
O O
O O
O
O O
O OH O
OH
O
HO OH
O
O
HO O
O

O
O
HO
O HO
O
O
O O
O
R 2O O O
O OR1
OH
OH
HO

Compound R1 R2
230 CA H
231 H CA

Batatins III and IV

As reported for all pentasaccharides from sweet potato (64, 86), pure compounds
232 and 233 were also submitted to saponification yielding simonic acid B (87).
The liberated fatty acids were identified as isobutyric, (2S)-methylbutanoic,
n-decanoic, n-dodecanoic, and cinnamic acids. The site of lactonization by the
aglycone in the macrocyclic unit was placed at C-2 of the second saccharide.
The position of the ester linkage on the macrocyclic unit was C-2 of the terminal
rhamnose. The acylations were identified as follows: for the macrocyclic unit at
C-2 of the third saccharide (n-dodecanoic acid), and at C-3 and C-4 of the branched
Resin Glycosides from the Morning Glory Family 119

terminal rhamnose ((2S)-methylbutyric or n-decanoic acids); for the glycosidic acid

at C-2 of the third saccharide (n-decanoic acid), at C-2 or C-3 (cinnamic acid), and
C-4 of the branched terminal rhamnose (isobutyric or (2S)-methylbutyric acids).

OH
O
HO O
O

O
O
HO
O O
O
O O
O O
R2O
R1O O O
OH
O
OH OH
HO O
O
HO O

O
O
O
HO
O OH
O
O O
R5 O O
4
R O O O
OR3
OH
OH
HO

Compound R1 R2 R3 R4 R5
232 mba deca CA H iba
233 deca mba H CA mba

Batatins V and VI

Batatins V (234) and VI (235) are acylated tetrasaccharide ester-type dimers

isolated from Ipomoea batatas, which yielded operculinic acid C through saponifi-
cation. A mild alkaline hydrolysis of both afforded compound 30, one of the
monomeric units, identified by coelution in HPLC with natural batatinoside III
(31), placing the lactonization at C-3 of the second saccharide in the macrocyclic
portion. C-3 of the third saccharide unit was identified as the position for the ester
linkage. Both dimers showed acylations at C-4 of the terminal rhamnose
120 R. Pereda-Miranda et al.

(n-dodecanoic acid) on the macrocyclic unit and at C-3 of the second sugar on the
glycosidic moiety (n-decanoic acid). Their diastereomeric structures, established by
the acylation pattern differences, were a consequence of the presence of n-decanoic
and n-dodecanoic acids at C-2 of the third sugar and C-4 of the terminal sugar on the
glycosidic acid (87).

OH
O
HO O
O

O
O
O
O OH
O

O OH O
O O
OH
O HO O
OH O
HO O

O
O
O O
O OH

HO O
O OR1
R2O
HO
OH

Compound R1 R2
234 dodeca deca
235 deca dodeca

Merremin

The methanol extract of the fresh tuber of Merremia hungaiensis Lingelish

and Borza was partitioned into a mixture of chloroform and water, and the chloro-
form-soluble resins were separated by silica gel and reversed-phase silica gel
chromatography. Purification by HPLC provided merremin (236), as the first
example of an ester-type dimer consisting of two units of operculinic acid A
partially acylated by four residues of palmitic (n-hexadecanoic) acid. Mild alkaline
hydrolysis of 236 gave tuguajalapin X (175) and its corresponding acylated glyco-
sidic acid. The aglycone lactonization site was placed at C-2 of the first L-rhamnose
unit in the macrolactone unit and the position for the glycosidic acid ester linkage at
C-6 of the terminal glucose. Both pentasaccharide units were acylated at C-2 of the
third sugar and C-4 of the branched terminal rhamnose (88).
Resin Glycosides from the Morning Glory Family 121

O
O

O
OH

O
HO

O
HO

O
O

O
O

OH
O

HO
OH
O
O

OH

O
O

HO

236
O
O

O
O
O

OH
OH

O
HO

HO

O
O

OH
O
O

HO
OH
O

OH
O

OH
O

HO
O

Tricolorins H–J

Investigation on the phytogrowth inhibitory polar fractions of heavenly-blue Ipomoea

tricolor Cav. (syn. Ipomoea violacea L.) allowed the isolation of three ester-type
heterohexasaccharides, tricolorins H–J (237–239), dimers of two trisaccharides,
either tricolorins F (10) or G (11), and tricoloric acid C. Each of the monomeric
units identified by coelution in HPLC with natural tricolorin G (11) and tricoloric acid
C were obtained through mild alkaline hydrolysis of 237. The aglycone lactonization
site was placed at C-2 of the third monosaccharide in the macrolactone unit and the
position for the glycosidic acid ester linkage at C-3 of the glucose unit. The terminal
L-rhamnose in the macrocyclic oligosaccharide was acylated at C-4 by (2S)-methyl-
butyric acid. The diastereomeric structures of tricolorins I (238) and J (239) were
dimers of tricoloric acid C, differing in the position of the ester linkage at C-3 or C-6
122 R. Pereda-Miranda et al.

of the glucose unit. Each of the monomeric units was identified as tricolorin F (10)
and tricoloric acid C through mild alkaline hydrolysis (22).

OH OH
O O
HO O O
HO
OH OH
HO O O O
HO O
HO O
O O
HO O
O
HO O
O
OH
O HO O

O
237

OH OH
O O
O O
HO HO
OH OH
O O O
HO HO O
HO O
O
HO O HO O
O O
HO HO
OH O

O
238

OH
O
O
HO
OH OH
O O
HO O
HO O
HO
O O O
HO O O
HO HO O
OH HO

HO O
O
HO
O

O
239
Resin Glycosides from the Morning Glory Family 123

4. Isolation Techniques

Resin glycosides are amphiphilic compounds because of the presence of long

aliphatic chains linked to a polar head. They are not very easy to isolate and purify
for they are always present as complex mixtures of homologues having the same
polar moiety but with alkyl substituents differing in chain length. Although a few
reports of the isolation of glycolipids using silica gel TLC exist, this procedure is
not suitable for purification of the individual constituents (89). Methods including
open and low-pressure column chromatography using silica gel, Sephadex, ion
exchange, and gel filtration were also conducted without successful results.
HPLC provides maximal resolution in a short-term analysis through the avail-
ability of small particle sizes (<25 mM in irregular and spherical shapes), pore sizes
(60 and 130 Å), and modified (silica-gel bonded) stationary phases. The major
technical challenges are finding the most favorable analytical factors (stationary
and mobile phases, isocratic or gradient modes of elution, and maximum sample
loading) and then scaling them into preparative conditions while retaining the
resolution. Normal phase (34) and C8 (27, 67), C18 (31, 69), cyano (51), and phenyl
(73, 88) silica gel bonded phases have been reported as being useful. As of now, the
most successful and commonly employed phase is the amino column (aminopro-
pylmethyl silica-bonded phase), a column also used for carbohydrate analysis.
Using this column, several commercial samples of Mexican jalaps were assessed
by generating HPLC profiles of their glycosidic acids, distinguishing the three
herbal drugs currently in frequent use and serving as analytical tools for their
authentication and quality control (10). Heart-cutting and peak shaving, singularly
or combined, have been employed in the purification of individual resin glycosides.
To achieve homogeneity, each peak collected is then recycled manually or using a
recycling valve (90) until overlapped components separate, as demonstrated by the
batatinoside (64), intrapilosin (65), murucoidin (71), orizabin (45), pescaprein (49),
and tricolorin (56) series.

5. Structure Elucidation of Resin Glycosides

The main approaches for the structure elucidation of the resin glycosides involve
the use of degradative chemical reactions or the application of high-resolution
spectroscopic and spectrometric techniques and combining both has proven to be
the best way for total characterization of these complex molecules.

5.1. Degradative Chemical Methods

Breaking up the large complex compounds by simple chemical reactions into

smaller, more manageable molecules, has developed as a result of the difficulties
124 R. Pereda-Miranda et al.

encountered in attempts to isolate the resin glycoside as intact constituents. Saponi-

fication of the crude material fragments the macrocyclic lactone and liberates the
fatty acids that esterify the oligosaccharide core, which is then subjected to acid
hydrolysis. Free fatty acids or their corresponding methyl or ethyl esters are
analyzed by GC-MS (10). Total acid hydrolysis of the glycosidic acids releases
the corresponding aglycone (hydroxylated C14 or C16 fatty acids) and monosaccha-
ride units. Chain size and exact positions of hydroxylation are determined through
direct EIMS analysis of the aglycone or GC-EIMS of its methyl ester and/or
trimethylsilyl derivatives. The sugar units are converted into volatile derivatives
by treatment with chlorotrimethylsilane and then analyzed by GC-MS. To avoid
normal acid hydrolysis anomerization, silylation of the hydroxy groups and mer-
captalation of the aldehyde functionalities is recommended (55). Liberated mono-
saccharides can also be detected by HPLC using a carbohydrate analytical column.
Protocols are available for sugar analysis by either method (91). Permethylation
of glycosidic acids followed by acid hydrolysis, pyranose reduction to the
corresponding alditols, and acetylation may be used to establish the number and
the relative positions of the glycosidic linkages (83). This allows the discrimination
between free hydroxy groups (which are methylated in the alditol) and those
involved in glycosidic bonds (acetylated in the alditols). Structure elucidation can
also be approached through: (1) partial acid hydrolysis providing degraded identi-
fiable products (di-, tri-, tetrasaccharides, etc.) (33); (2) partial basic hydrolysis of
ester linkage in dimeric forms to correlate with natural monomers (78, 88); and (3)
total synthesis of the oligosaccharides (24, 25).

5.2. Spectroscopic Methods

Complete structure elucidation of individual resin glycoside constituents is now

achieved readily by the use of a combination of high-resolution mass spectrometry
and NMR spectroscopy. These methods are applicable to the isolated natural
products or to their peracetylated and methylated derivatives.

5.2.1. Mass Spectrometry

Natural glycoresins, even those having up to four acyl substituents, are polar solids
with melting points generally above 100 C and are consequently non-volatile and
quite difficult to vaporize in a standard electron-impact ion source without being
thermally damaged. Electron ionization is not a suitable analytical method for these
compounds even though their peracetyl and permethyl derivatives are easily vola-
tilized and ionized (59, 86, 92). Soft ionization techniques, as fast-atom bombard-
ment (FAB) and electrospray ionization (ESI), made a dramatic contribution to the
field of resin glycoside characterization. The sample ions are formed as protonated
Resin Glycosides from the Morning Glory Family 125

(positive mode) and deprotonated (negative mode) molecular species. The major
breakthrough in FABMS analysis was due to the use of a liquid matrix, which
facilitates production of molecular ions of the solute, helps in maintaining a
persistent emission of these solute molecular ions, and allows dissipation of impact
energy of the primary beam. Glycerol, the matrix most commonly used, is the best
choice for underivatized oligosaccharides in the positive mode. Other alternative
matrices for hydrophobic samples are 3-nitrobenzyl alcohol (3-NOBA), thiogly-
cerol, and triethanolamine. Mass spectrometric quality depends on the pH, which is
regulated by trace additions of HCl, and on the ionic force of the matrix, which may
be increased by impregnation of the targeted sample with methanolic solutions of
NH4SCN, NaCl, or NaOAc. These additives promote the formation of abundant
pseudo-molecular cations such as [M + H]+, [M + Na]+, and [M + NH4]+ or anions,
such as [M + SCN], and also facilitate the characteristic fragmentation of the
glycosidic linkages for diagnostic purposes (93, 94). The use of triethanolamine
leads to a desirable extensive oligosaccharide fragmentation in the negative mode
critical for identification of the glycosidation sequence (49, 64). The numbers of
units in these pure oligomers, as well as for total crude mixtures of resin glyco-
sides, are obtainable through detection of molecular and fragment ions (95).
Electrospray ionization also provides such structural information as composition,
sequence, branching of the oligosaccharide, and type of sugar linkages. The
reported mass spectra of batatins illustrate what can be expected from the analysis
of an ester-type dimer in the negative mode (see Fig. 1): the [M – H] anion, the
glycosidic cleavage peaks, the fragments for the fatty acid elimination, and the
[M/2 – H] peak, representing the high-mass fragment ion for the two monomeric
units (78).

m/z 1197 m/z 545 m/z 417

O O
Dodeca Mba C
1379.79
100 (CH2)9
1249.77 Cna Rha’’ Rha’ Rha Fuc O CH
1380.82
m/z 1249 (CH2)4
Rha’’’
CH3
O

Dodeca Mba O C m/z 1379

417.32
(CH2)9
%
1381.85 Cna Rha’’ Rha’ Rha Fuc O CH
(CH2)4
Rha’’’
1197.62 CH3
126.92 1382.84
545.37
2761.61

0 m/z
250 500 750 1000 1250 1500 1750 2000 2250 2500 2750 3000 m/z

Fig. 1. Negative-ion MS/MS ESImass spectrum of batatin I (230). This technique provides an
easily detectable [M  H] peak (m/z 2761.61). All the characteristic ions resulting from
glycosidic cleavage are clearly observed. The high-mass ion [M/2 – H] (m/z 1379.79) corre-
sponds to the ester cleavage of the dimeric structure. From Escalante-Sánchez and Pereda-
Miranda (2007), with permission of the American Chemical Society (78)
126 R. Pereda-Miranda et al.

5.2.2. Nuclear Magnetic Resonance

Due to extensive overlap within the region d 3.0–4.5 ppm, 1H NMR spectra of
oligosaccharides in many cases produce complex patterns. In one-dimensional
NMR analysis, the solvent pyridine-d5 improves signal dispersion better than
methanol-d4 or acetone-d6. For structural analysis, the following steps are sug-
gested:
1. Estimation of sugar units: the anomeric protons around d 4.4–6.5 ppm can be
used as “structural reporter groups” for signals outside the bulk region. The
integration of each of these resonances allows estimation of the number of
different monosaccharide residues. The observed coupling constant values for
the anomeric resonances are distinctive for each monosaccharide type: 1.0–
3.0 Hz for rhamnose, 7.0–8.0 Hz for fucose, and 8.0–9.0 Hz for glucose and
quinovose. In the 13C NMR spectra, the anomeric signals in the d 98–105 ppm
region directly indicate the number of monosaccharide units. Sensitive 2D
13
C-1H NMR experiments using HSQC, HMQC, or HMBC provide the same
data. Profiling of the resin glycoside content of Mexican jalaps was assessed by
generating 13C NMR spectra of their glycosidic acid derivatives (10).
2. Identification of constitutive monosaccharides: two-dimensional homonuclear
NMR techniques such as DQF-COSY and TOCSY are used to assign chemical-
shift values for all C-bonded protons in each individual monosaccharide (96).
One-dimensional NMR spectra provide useful information about the chemical
shifts and scalar couplings of such well-resolved signals as methyl groups for
6-deoxy monosaccharides (fucose, quinovose, and rhamnose) at d 1.1–1.3 ppm.
3. Characterization of anomeric configuration: in D-pyranoses in 4C1 conformation,
the a-anomer resonance appears downfield in comparison with the b-anomer
(96). The vicinal coupling constant between the anomeric H-1 and H-2 protons
indicates their relative orientation, i.e., a large coupling constant value
(J = 78 Hz) for an axial orientation and smaller values for the axial-equatorial
(J = 4 Hz) or equatorial-equatorial (J = <2 Hz) ones. The 13C-1H (1JCH)
coupling constant is a more reliable criterion to determine conclusively the
anomeric configuration in pyranoses. For D-sugars in the 4C1 conformation,
the a-anomeric configuration (b-equatorial C–H bond) has a 1JCH value of
170 Hz, which is 10 Hz higher than that observed (1JCH = 160 Hz) for the
b-anomer (a-axial C–H bond). This difference is reversed for L-sugars. One-
bond rhamnose coupling constants correlate the anomeric configuration, which
is impossible to deduce from the almost identical 1H–1H coupling values
(3J = >2 Hz) or the 13C NMR chemical shifts for both anomers.
4. Elucidation of glycosidation sequence: the effect on the proton chemical shift of
glycosylation is a typical deshielding (0.1–0.4 ppm) of the proton across the
glycosidic bond (97). Glycosylation sites can be identified by comparison of
1
H NMR spectra of the native and the peracetylated oligosaccharide, since
acylation of the free OH causes a downfield shift (0.5–1 ppm) of hydroxy-
substituted geminal protons, whereas a-protons directly involved in the glyco-
sidic linkage remain almost unaffected, permitting identification of both sites of
Resin Glycosides from the Morning Glory Family 127

glycosylation as well as signals of terminal sugar residues. HMBC studies

established the interglycosidic connectivities on the basis of long-range (3JCH)
heteronuclear coupling correlations (96). Interresidue nuclear Overhauser
effects in NOESY and ROESY experiments also provide glycosidic linkage
and anomeric configuration. In addition, ROESY crosspeaks discriminate
between the a- and b-anomers of rhamnopyranosyl units (96).
Ester-type dimers illustrate the four-step approach for identification of carbohy-
drate structural elements in the oligosaccharide cores by NMR spectroscopy. For
these type of compounds, edited 1H NMR sub-spectra have permitted the assign-
ment of all of the resonances in both monomeric units (22, 78). Spectroscopic
simulation of the coupling constants can be deduced for proton resonances with a
non-first-order resolution. Figure 2 illustrates this approach for batatin I (230); the

AB A AB AB
H1 H3 H2 H5
Rha BA BA
Rha’ H2 H2 H1 H1
A B A A B B
Rha’’ H4 H2 H1 H3 H1 H4
A AB A
Rha’’’ H1 H1 H3 H2
AB
Fuc H1 H1

6.35 6.30 6.10 6.05 6.00 5.95 5.90 5.85 5.80 5.75 5.70 5.65 5.60 5.55 5.35 5.30 5.05 5.00 4.85 4.80 4.75 d/ppm
Rha AB Fuc AB

Rha’ AB

Rha’’ AB
Rha’’’ AB

6.35 6.30 6.10 6.05 6.00 5.95 5.90 5.85 5.80 5.75 5.70 5.65 5.60 5.55 5.35 5.30 5.05 5.00 4.85 4.80 4.75 d/ppm

Fig. 2. Simulation of the anomeric region of the 1H NMR spectrum of batatin I (230). The top
trace is the measured 500 MHz spectrum, resolution enhanced. Actual chemical shifts are depicted
along the bottom of the top plots. Below are the simulated spectra for each of the units. The Hn
descriptors denote a specific position for each sugar unit. From Escalante-Sánchez and Pereda-
Miranda (2007) with permission of the American Chemical Society (78)
128 R. Pereda-Miranda et al.

coupling constants were varied by employing the MestRe-C program until an

optimal agreement was achieved for the second-order analysis between measured
and calculated spectra (78).
High-field NMR application of Mosher’s method was used to demonstrate that
the absolute stereochemistry for all the hydroxy groups in the resin glycoside fatty
acids correspond to the (S)-configuration (70, 98), e.g., (11S) for jalapinolic and
convolvulinolic acids and (3S,11S) for dihydroxylated fatty acids such as ipurolic
acid. This resulted in the revision of the (R)-configuration originally proposed by
Horeau’s method for jalapinolic acid (13).

5.3. Crystallographic Methods

X-ray diffraction by single crystals is by far the most powerful experimental

method for the characterization of atomic arrangements in molecules, providing
accurate data concerning the conformation of carbohydrates. This information
includes precise atomic coordinates, geometries, and crystal packing in the solid
phase (99) and has the advantage over NMR spectroscopy in that it provides
complete oligosaccharide conformation from experimental data. Its limitation is
the requirement for regular crystals since few underivatized oligosaccharides crys-
tallize uniformly due to their inherent flexibility. Obtaining a pure useable amount
of an individual resin glycoside sample for crystal growth is a huge challenge and
tricolorin A (106) is the only Convolvulaceous oligosaccharide that has been
characterized crystallographically (100).
Four independent conformations were found in the asymmetric unit cell (see
Fig. 3), but their superposition showed that all shared the same global shape (see
Fig. 4), albeit with slightly different conformations for the externally placed
L-rhamnopyranosyl-(1!3)-O-a-L-rhamnopyranoside moiety. The internal trisac-
charide subunit, L-rhamnopyranosyl-(1!2)-O-b-D-glucopyranosyl-(1!2)-O-b-D-

Fig. 3. Graphical representation of a unit cell showing the presence of 18 water molecules in the
asymmetric unit in addition to the four independent tricolorin A (106) molecules
Resin Glycosides from the Morning Glory Family 129

Fig. 4. Superposition of the four independent molecules of tricolorin A (106) showing that the
internal trisaccharide subunit has limited conformational freedom due to its macrolactone structure

Fig. 5. Two different views (ca. 180 ) of a single tricolorin A (106) molecule. Left, hydrophilic
face. Right, hydrophobic face. Protons of hydroxyl groups are colored in cyan

fucopyranoside, has limited conformational freedom due to its macrolactone struc-

ture that spans the terminal two saccharide units reducing flexibility but allowing a
uniform packing in the unit cell. The aglycone portion is well preserved in contrast
to the flexibility for the terminal n-pentyl chain. Each molecule exhibits a hydro-
phobic wall formed by the aglycone unit, the methyl group of the fucose unit, and
the three lipophilic residues on the inner rhamnose unit, i.e., the methyl group and
the two esterified (2S)-methylbutyric acid groups. The other face presents two small
hydrophilic areas: one composed of the hydroxy groups of the fucose and glucose
residues and the other of the external rhamnose unit (see Fig. 5).
Notable in the tricolorin A (106) solid state is the presence of 18 water molecules
in the unit cell, and an anisotropic repartitioning of the hydrophobic and hydrophilic
sections. The water molecules form a dense network that creates a dividing layer
between the hydrophilic faces (see Fig. 6). The high water content indicates that
the conformation in the solid state is not dominated by intermolecular forces and
could be indicative of a similar conformation in both solution and supermolecular
130 R. Pereda-Miranda et al.

Fig. 6. Anisotropic repartitioning of the hydrophobic and hydrophilic interfaces observed in the
crystal packing arrangement of tricolorin A (106)

aggregates. Conformational rigidity imposed by the macrolactone was also evident

in the crystal structure of the synthetic substructure of tricolorin A, consisting of a
protected disaccharide, 4,6-O-benzylidene-b-D-glucopyranosyl-(1!2)-(3,4-O-iso-
propylidene)-b-D-fucopyranoside. Five independent molecules were refined for the
asymmetric unit of this analogue and confirmed the preservation of the macrocyclic
moiety conformation. A piled parallel arrangement of the glycoside residues on one
side and the macrolactone rings with alternating a- and b-faces on the other side
was observed (101).

5.4. Molecular Modeling

Many force fields have been developed as well as protocols for modeling oligo-
saccharides (99, 102), but it is necessary to modify them to include the exo-
anomeric effect that largely determines the torsion angle f of the glycosidic linkage
(103). Although the X-ray f/c plots indicate a wide range of glycosidic linkage
conformations a smaller one might be adopted. For example, as dictated by the exo-
anomeric effect, the energy maps of the three disaccharide subunits of tricolorin A
(106) differ, and display low-energy regions centered around a f-axis gauche
conformation. A higher level of conformation freedom is apparent along the c
axis with the lowest energy region between 60 and 180 contrasting with the
limited flexibility for the macrocyclic trisaccharide in this part of the 19-membered
ring. Similar conclusions were obtained from the crystal structure of the synthetic
dimeric subunit of tricolorin A since the glycosidic bond geometry in all five
independent conformations was predicted by the exo-anomeric effect for the torsion
angle f. The other torsion angle populates the range 53 –76 , limiting the flexibil-
ity of the macrolactone (100).
Resin Glycosides from the Morning Glory Family 131

A combined approach is to use interproton distances determined by simulation

and experimental NOE intensities to calculate the dynamic behavior of specific
linkages in an oligosaccharide. The MM force field was employed for the computer
simulation of calonyctin A1 (40) where interglycosidic NOEs served as experimen-
tal distance restraints for the molecular dynamics (104).

6. Strategies for Synthesis

Resin glycoside macrolactone rings present a major challenge to develop meth-

odologies for their synthesis. Initially, as employed for the total synthesis of
calonyctin A2 (41) (105), tricolorin A (106) (106, 107), and tricolorin F (10)
(108), these rings were prepared by conventional macrolactonization techniques,
relying on the intrinsic differences in reactivities of the oligosaccharide core
hydroxy groups and resulting in a regioselective process. This approach was
obviously limited for the formation of a wide range of structural analogues since
each new compound requires an independent multistep synthesis (coupling reac-
tions of carbohydrate building blocks).
An alternative methodology takes advantage of the inherently modular character
of ring-closing alkene or alkyne methathesis (RCM). Systematic variations of ring
size and hence of target molecule lipophilicity are easy to produce by macrocycli-
zation reactions via RCM using a ruthenium-based precatalyst compatible with the
secondary hydroxy functions of sugars. The total syntheses using this approach of
tricolorin A (106) (109), tricolorin G (11) (110), woodrosin I (228) (111, 112), and
ipomoeassins B (3), and E (6) (113) as well as the synthesis of the most frequently
found disaccharide unit, L-Rha-(1!2)-D-Fuc, started with sugar building blocks
(i.e., L-rhamnose, D-fucose and/or D-glucose) and (6S)-undec-1-en-6-ol (110, 114),
with the latter readily accessible via asymmetric synthesis.

6.1. Tricolorin A

The total synthesis of tricolorin A (106) is an illustration of both synthetic

approaches. The key disconnection for its retrosynthetic analysis (Scheme 1) has
been the glycosidic linkage between glucose and rhamnose units. Coupling a
rhamnose-rhamnose disaccharide glycosyl donor with a lactone disaccharide gly-
cosyl acceptor has been used for the assembly of the entire tetrasaccharide skeleton
of this target molecule. Both disaccharide subunits have been assembled via
established glycosidation strategies. Due to the steric impediment that the large
substituent at the anomeric position would present at the C-2 hydroxy group of the
glucose unit, retrosynthesis of the lactone disaccharide fragment used the intrinsic
differences in reactivities of the glucose hydroxy groups to selectively form the
macrolactone at C-3 in the first approach, thus minimizing the number of protecting
132 R. Pereda-Miranda et al.

C5H11
OH
O
O
HO
HO
O O
HO
O
O O

O
O
O O
O
O O
HO
HO
106
OH

RCM

X C5H11
OR
O O
O O
RO
O O RO
O O
RO O
O O O
HO
O OH
HO OH

LACTONIZATION

C5H11 CO2H
RO C5H11
O OR
O
RO O
RO O
O O RO
RO
RO
O O O
OH RO
O HO
OH

Scheme 1. Retrosynthetic analysis of tricolorin A (106)

Resin Glycosides from the Morning Glory Family 133

groups. The RCM approach used an adequate diene as a cyclization precursor

prepared by selective acylation with heptenoic acid of the corresponding diol at
C-3 of glucose, in full accordance with the reactivity pattern described above.

6.1.1. Macrolactonization

The macrolactonization approach has been used by two different groups (106, 107)
to synthesize tricolorin A (106). Both approaches are similar and used as a key
disconnection the glycosidic linkage between the glucose and rhamnose rings, and
their goals were not to develop new synthetic methodologies for carbohydrates but
rather to apply the known chemistry in an efficient manner. Larson and Heathcock
started by coupling of the methyl ester derivative of jalapinolic acid with a
protected D-fucosyl trichloroacetimidate to form fucoside 240 (106). Removal of
the C-2 pivaloyl group from this derivative, followed by coupling with D-glucosyl
trichloroacetimidate 241, resulted in isolation of disaccharide 242. The reaction of
disaccharide glycosyl trichloroacetimidate 243 with disaccharide 242 was used to
assemble the tetrasaccharide core. In preparation for the macrolactonization, the
four ester groups were saponified to give acid triol 244. Following the Yonemitsu
protocol, the trihydroxy acid lactonized with a high degree of selectivity at the C-3
hydroxy position of the glucose ring instead of at the C-2 position, to afford the
target diester lactone 245, which was produced after addition of the chiral side
chain acid. Synthetic tricolorin A (106) was obtained by deprotection of 245.
Starting from fucose, glucose, rhamnose, and (3S)-1-octyn-3-ol, the synthesis
required 38 steps overall. The longest linear sequence was 14 steps, with an overall
yield for this linear sequence of 6% (Scheme 2).
Coincidentally, Lu and co-workers employed a similar strategy for assembling
the macrolactone disaccharide subunit (246) through a regioselective macrolacton-
ization by the Corey–Nicolaou protocol (107). Macrolactone tetrasaccharide 245
was finally assembled by a facile one-pot, two-step glycosylation process with
thioglycoside donors 247 and 248. Alternatively, 245 was also constructed step-
wise; disaccharide synthon 249, the intermediate in the above one-pot protocol, was
efficiently synthesized by a reaction of 247 and 248 involving the armed-disarmed
glycosidation approach. Glycosylation of macrolactone disaccharide 246 by di-
saccharide donor 249 afforded the same important protected macrolactone precur-
sor 245 of tricolorin A (106). This synthesis was achieved in a total of 45 steps,
where the longest linear sequence consists of 20 steps, and the overall yield was
0.65% starting from D-(+)-mannitol (Scheme 3).

6.1.2. Ring-Closing Alkene Metathesis

RCM was also employed as a key design element for the synthesis of tricolorin A
(106). This novel strategy demonstrated the efficiency of macrocyclizations using
the standard ruthenimum catalysis either by the classical Grubbs carbene com-
plex or the recently developed cationic ruthenium allenylidene complex as the
134 R. Pereda-Miranda et al.

O
d, e O
Ph O
O O
O
AcO O HO
O HO
O OH OH
HO OH
OEt k, l, m
a, b, c
f
OC(NH)CCl3
O
Ph O 241
O O
+ BnO O
O AcO
AcO BnO OBn OAc
HO OC(NH)CCl3
OAc
g,h

CO2CH3
O n,o C5H11
p,q O
O O
AcO O
O OAc
O 240
OH
O
BnO CO2CH3
BnO OBn C5H11
O
i, j O
O
Ph O O
O
O O
OC(NH)CCl3 + AcO
OH
242
O
AcO
O OAc
O r, s
BnO
BnO OBn
243
CO2H
C5H11
C5H11
O
O
O
O O
O O
Ph O O
Ph O
O
O O O
O O O
HO
O O O
w t
O
106 O O
HO
O O
O O OH
O O
BnO O
BnO 244
BnO OBn 245 BnO OBn

Scheme 2. Conditions: (a) BnBr, Bu4NI, NaH, DMF; (b) (i) t-BuOK, DMSO, 100 C; (ii) 1N HCl,
acetone, reflux; (c) Cl3CCN, Cs2CO3, CH2Cl2, 76%; (d) (EtO)3CMe, p-TsOH, CH2Cl2; (e) Ac2O,
Et3N, DMAP, CH2Cl2; (f) HOAc, H2O, 77%; (g) BF3-Et2O, CH2Cl2; (h) NaOMe, MeOH, 81%; (i)
(Ph3P)3RhCl, n-BuLi, THF, reflux; (ii) HgO, HgCl2, acetone, H2O; (j) Cl3CCN, Cs2CO3, CH2Cl2,
95%; (k) Ac2O, Et3N, DMAP, CH2Cl2; (l) (i) BnNH2, THF; (ii) 1N HCl; (m) Cl3CCN, Cs2CO3,
CH2Cl2; (n) (i) 240 (ii) AgOTf, CH2Cl2; (o) LiOH, THF, H2O; (p) Ac2O (1 equiv), Et3N, DMAP,
CH2Cl2; (q) NaOMe, MeOH, MeOAc; (r) TMSOTf, CH2Cl2; (s) LiOH, THF, H2O; (t) (i) 2,4,6-
trichlorobenzoyl chloride, Et3N, DMAP, benzene; (ii) (S)-2-methylbutyric acid; (w) Pd(OH)2, H2,
HCl, MeOH

precatalysts (110). The required cyclization precursor 251 of the macrolactone

disaccharide subunit 246 was assembled by established glycosidation methods
from D-glucose, D-fucose, and (6S)-undec-1-en-6-ol (109). Diene 251a cleanly
Resin Glycosides from the Morning Glory Family 135

SEt SEt
b
O O
BnO + O 249
BnO HO O
OBn O
O
247 248
a c

SEt
O
O
O C5H11
O O
O
O O O
BnO a O d
BnO O
249 OBn Ph O 106
O
+ O O
O
C 5 H 11 O O
O
O
O O
O
Ph O O O
O O
O
O O O O
O BnO
O OH 246 BnO OBn 245

Scheme 3. Conditions: (a) 247 (1,2 equiv), 248 (1.0 equiv), NIS (1.4 equiv), TfOH (cat.), 4-Å
molecular sieve, Et2O, DCE (1:1; DCE = 1.2-dichloroethane), 15 C, 15 min, then 246 (1.6
equiv), NIS (1.4 equiv), TfOH (cat.), 4-Å molecular sieve, RT, 1 h, 43% (based on 246); (b) IDCP
(2.3 equiv), 4-Å molecular sieve, CH2Cl2, RT, 0.5 h, 98%; (c) (i) donor 246, (ii) NIS (4.5 equiv),
AgOTf (0.5 equiv, 4-Å molecular sieve, CH2Cl2, RT, 1 h, 86%; (d) two steps 1. DDQ (3.0 equiv),
CH3CN/H2O (9/1), reflux, 4 h, 80%; 2. H2 (6 Mpa), 10% Pd/C, 60 C, 7 h, 88%

cyclized to the desired 19-membered ring on reaction with the ruthenium carbene
252. The fact that neither the free hydroxy group nor any other functional group in
the substrate interfered with the RCM illustrated the selectivity of the Grubbs
catalyst. Hydrogenation of the crude cycloalkene ((E)/(Z)-mixture) afforded disac-
charide 246 in 77% yield over both steps. Since 246 was used as the key disaccha-
ride subunit in the synthesis of 106 by the macrolactonization approach (see,
Sect. 6.1.1), this RCM-based methodology completed a formal total synthesis of
tricolorin A (Scheme 4). It should be mentioned that regioselective esterifications
of diol 253, in full accordance with Heathcock’s observations, with acids other
that 4-pentenoic acid (251a–251c), permits a convenient entry into tricolorin A
analogues differing from the parent macrolactone compound in their lipophilicity,
as exemplified by the synthesis of compound 254 with a smaller macrocyclic
structure, and 255 with an expanded lactone moiety.

6.2. Ipomoeassin E

The route for the cytotoxic ipomoeassin resin glycosides relied on the use of
compound 256 as a new cinnamic acid surrogate with its trisubstituted double
bond and meets the requirement of being hydrogenation resistant in the presence
136 R. Pereda-Miranda et al.

C5 H 11
O C5H11
O O
O
O O
O
OH a Ph O
O
+ O
O O
Ph AcO 253
O
O OAc
O O CCl3
AcO
OAc NH b

C5H11
C5H11
O
O
O
O c, d O
O O
O Ph O
Ph O O
O O O
251 a n=1
O O
O
O b n=3
246 n OH c n=7
OH
O O
c, d PCy3
Cl 252
c, d Ru
Cl CPh2
PCy3

O
C5H11
O O
O O C5H11 O
Ph O O
O O
O O Ph O
O O
O O
OH O
O 254 OH 255
O

Scheme 4. Conditions: (a) BF3·Et2O cat., 20 C, CH2Cl2/n-hexane, 82%; (b) DCC, DMAP,
CH2Cl2, 251a, 4-pentenoic acid, 80%; 251b: 6-heptenoic acid, 71%; 251c: 10-undecenoic acid,
67%; (c) catalyst 252, CH2Cl2, reflux; (d) H2 (1 atm), Pd/C, EtOH, 246: 77% (over both steps);
254: 76% (over both steps); 255: 76% (over both steps)

of homogeneous catalysts (113). As expected, acylation of disaccharide 257 with

tiglic acid occured preferentially at the 300 -OH site (258). Reductive opening to the
substituted benzylidene acetal in product 258 afforded the corresponding 600 -OPMB
ether (259). Attachment of 256 to this derivative produced 260, which was followed
by oxidative cleavage of the -OPMB ether, released primary alcohol 261. The
subsequent following steps for the preparation of the required chiral acid segment
for the esterification of this primary alcohol were: a Sharpless-type kinetic resolu-
tion of furyl alcohol ()-262; oxidative rearrangement of ()-262; oxidation of the
hemiacetal in 263; conjugate reduction of the resulting enone; opening of the
>
Scheme 5. Conditions: (a) Tiglic acid, DCC, DMAP, CH2Cl2, 55%; (b) NaBH3CN, TMSCl, 4-Å
molecular sieve, MeCN, 62%; (c) Acid 256, 2,4,6-trichlorobenzoyl chloride, Et3N, DMAP,
toluene, 79% (over both steps from 258); (d) DDQ, CH2Cl2/H2O; (e) t-BuOOH, VO(acac)2
(2%), CH2Cl2, 71%; (f) CrO3, H2SO4, acetone, 0 C; (g) Zn, HOAc, CH2Cl2, 78% (over both
steps); (h) (i) HO(CH2)2SiMe3, p-TsOH cat., CH2Cl2; (ii) Ac2O, DMAP cat., CH2Cl2, 93% (over
both steps); (i) TASF, DMF, 68%; (j) compound 261, 2,4,6-trichlorobenzoyl chloride, Et3N,
DMAP, toluene, 87%; (k) complex 268 (10%), CH2Cl2, reflux, 85%; (l) H2 (1 atm), RhCl
(PPh3)3 (20%), EtOH, 83%; (m) TASF, MeCN; (n) TFA, CH2Cl2, 63% (over both steps)
Resin Glycosides from the Morning Glory Family 137

O O
O a O
O C3H7 O C3H7
R O BST O
O O
O O
O O
HO O O
O
OH 257 O OTSB
258
R=p-MeOC6H4-
b

O O
O O
PhMe2Si O O C3H7 O C3H7
O PMBO O
RO
O O
Ph O c HO
O O O O

O OTSB O OTSB
PhMe2Si O

Ph OH 259
260 R=PMB 256
d
261 R=H
OH O
OH
e O f, g O
O

O O
(-) -262 263 264

h
O
O
AcO
O
O C3H7
O O O
O j O
O
Ph O OR
O O
OAc O
O OTSB

265 R=CH2CH2SiMe3
267 Mes N N Mes i
Cl 266 R=H
k, l Ru
Cl Ph
PCy3
O OAc 268

O
O O C3 H7 m, n
O
PhMe2Si O
O O 6
O
Ph O
O O

O OTSB

269
138 R. Pereda-Miranda et al.

lactone 264; and cleavage of ester 265, producing a good overall yield of acid 266
without racemization of the rather labile center at C-5. Esterification of 266 with
disaccharide 261 afforded the precursor 267 for RCM macrolactonization using the
ruthenium carbene 268. Hydrogenation of the resulting (E)/(Z) mixture afforded
macrolactone 269 which, after simultaneous cleavage of the C-silyl and O-silyl
groups as well as final deprotection of the isopropylidene acetal, afforded ipomeas-
sin E (6) in high overall yield (Scheme 5).

6.3. Woodrosin I

This particular branched oligosaccharide is certainly the structurally most demand-

ing resin glycoside to have been totally synthesized (111, 112). The particular
challenges were: (1) the large macrolide ring spanning four glucose units; (2) the
complementary acylation pattern at its periphery which seriously restricted the
choices for protecting groups; (3) the pentasaccharide core entailing severe steric
hindrance among hydroxy groups at vicinal positions at the branching site. Treat-
ment of substrate 270 with tichloroacetimidate 271 resulted in a regioseletive
reaction of the glycosyl acceptor’s vicinal diol unit. Surprisingly, the reaction
exclusively delivered the orthoester 272 by participation of the adjacent chloro-
acetyl moiety rather than the expected b-glycoside. Inspections of models suggested
that the trajectory of a glycosyl donor towards the hidden 200 -OH group might be
more favorable after closing the macrocyclic ring. Therefore, the completion of the
oligosaccharide core was postponed after the RCM reation. Diene 272 was treated
with catalytic amounts of the ruthenium indenylidene complex 273 resulting in an
efficient ring closure which afforded cycloalkene 274 in 94% yield, (E):(Z) = 9:1
(Scheme 6). An inverse glycosylation procedure was used for the condensation of
alcohol 274 and donor compound 275. This method allowed for the attachment of
the missing rhamnose unit to the oligosaccharide backbone as well as for the
concomitant rearrangement of the orthoester to the required b-glycosidic linkage
in the isolated product 276, which was then easily elaborated into woodrosin I (228)
(Scheme 6).

7. Significance

Little is known about either the mechanism of the purgative action caused by resin
glycosides of the morning glory family or their ecological significance for the
producing plants. The discovery of physiological effects with therapeutic potential

>
Scheme 6. Conditions: (a) donor 271, TMSOTf cat., CH2Cl2, 84%; (b) complex 273 cat., CH2Cl2,
reflux, 94%; (c) donor 275, TMSOTf cat., Et2O, 0 C, 60%; (d) hydrazinium acetate, DMF,
10!0 C; (e) H2, Pd/C, MeOH, 84% (over both steps)
Resin Glycosides from the Morning Glory Family 139

OBn
BnO

BnO
C5H11
OBn O O O
BnO O O
O + O
Ph BnO
O O O
O O NH
O O O
PMBO O O CCl3
OH
270
O
271
Cl

BnO BnO
C5H11
O OBn
BnO O
O O
Ph BnO
BnO O O O
O
O O O
O O O
O
O OH 272
O

O
Cl PCy3
Cl
Ru
b Cl
PCy3

273

BnO BnO O
C5H11
OBn
BnO O
O O
Ph BnO
BnO O O O
O
O O O
O O O
O
O OH 274
O

O O NH
Cl
O
O O CCl3
c BnO O O
275
OBn
BnO

O
BnO C 5 H 11
O OBn
O O
BnO
O
O Ph BnO
O O
O
O O O O
O
O
O OR O d, e
O
228
O O
BnO O O
276, R=COCH2Cl
140 R. Pereda-Miranda et al.

has stimulated a scientific revival of chemical research and biological evaluation of

these principles. As of now, nothing is known about the biosynthesis of these
compounds and all that can be said is that they are secondary metabolites derived
from the assembly of products of primary metabolism such as sugars and fatty
acids.

7.1. Traditional Medicine and Morning Glories

Morning glories have worldwide recognition in traditional medicine for the treat-
ment of several illnesses apart from their purgative properties. Following is a
description of the most interesting ethnobotanical information concerning resin
glycoside-containing species.
In the Old World, several species are included in the contemporary health care
systems of countries like the People’s Republic of China and India, which have a
long history of traditional use of herbal drugs. For example, the seeds of Cuscuta
chinensis and C. japonica are used as tonics in mainland China (14). Merremia
hungaiensis is the Chinese crude drug “Tu Gua” and used for the treatment of
chronic hepatitis, hernia, and dealing with the tantrums of children (73). In the
Unani system of India, C. chinensis is also considered to have antitumor activity.
The seeds of I. nil are regarded as diuretics and antihelminthics as well as being
prescribed for edema, constipation, and to promote menstruation (77, 86). In India,
the seeds of I. turbinata and I. hederacea are also used as laxatives and carmina-
tives. In Indonesia, the tuber of I. mammosa is used to treat diabetes and illnesses
involving the throat and the respiratory system as well as for burns, dysentery,
edema, fever, and snake bites (24). Convolvulus microphyllus is reported to be a
prominent memory-improving drug and used as a psychostimulant and tranquilizer
as well as to reduce mental tension (61). In Europe, Calystegia soldanella has been
used to cure hydropsy, paralysis, rheumatism, and scurvy (81). Worldwide, Ipo-
moea pes-caprae, commonly called “railroad vine” or “beach morning glory”, is
used in infusions for urinary or kidney complaints, hypertension, and scrofula and
in decoctions to treat functional digestive disorders, internal pain, colic, dysentery,
lumbago, and arthritis, rheumatism and other inflammatory conditions (29, 49,
76, 80).
In the New World, several morning glories have been used since pre-Hispanic
times. Native Americans used primarily the roots of I. leptophylla, e.g., the Pawnee
tribe dried the roots, burned them, and inhaled the smoke for treatment of ner-
vousness and the Lakota people ate portions of the roots for stomach ailments
(66). In Mexico, the roots of I. orizabensis have been employed as a vermifuge,
for abdominal inflammation, dysentery, epilepsy, hydrocephaly, meningitis, and
tumors (44). The roots of I. stans have been used to treat convulsions, hypertension,
epilepsy, St. Vitus’ dance and other nervous afflictions (53). There are 13 tree-like
morning glory species belonging to the series Arborescentes with most confined to
Mexico and nearby Central America. I. murucoides represents the signature species
Resin Glycosides from the Morning Glory Family 141

Plate 3. Arborescent morning glory species. The 13 species are confined to Mexico and nearby
Central America and have long been of medicinal and economic interest (A: flowering tree in the
archeological zone of Monte Alban, Oaxaca, Mexico). In central Mexico, six species collectively
called “cazahuate” are a conspicuous floristic element of the Seasonal Dry Tropical Forest
(B: Watercolor from eighteenth century Spanish Royal Botanical Expedition to the New World
where the native name “Quahutzehuatl” was used to identified Ipomoea murucoides, the signature
species of this medicinal plant complex. Courtesy of Hunt Institute for Botanical Documentation,
Carnegie Mellon University, Pittsburgh, PA. Torner Collection of Sessé and Mociño Biological
Illustrations). These trees share the morphological features of large white flowers and funnel-
shaped corollas (C), as well as the same therapeutic uses such as treating itching and rashes by
rubbing the raw flowers directly on the skin. Dried flowers with fruits (D)

of the “cazahuate” medicinal plant complex, a Nahuatl word (Aztec language) for
“tree to cure mange” (Plate 3). This vernacular name in contemporary Mexican
Spanish is used for all medicinal arborescent morning glories that share two
142 R. Pereda-Miranda et al.

therapeutic properties: the raw flowers, used antiseptically, are rubbed directly on
skin infections, itches and rashes, and as decoctions, plasters, and poultices for
rheumatism, inflammation, and muscular pain (70). I. arborescens is another
member of the “cazahuate” complex also known in several states of Western
Mexico as “palo bobo”. Some communities use an aqueous infusion of the bark
against snake and scorpion bites, and to prevent hair loss (58). Infusions prepared
from leaves are used as an anti-inflammatory agent and to treat stomachache.
I. intrapilosa is endemic to the “Sierra Madre Occidental” (Western Sierra
Madre, Mexico) and also grows in the central volcanic region that includes the
states of Michoacán and Morelos. An infusion of the flowers of this “cazahuate”
is used topically to treat rheumatism and ear pain, and the bark is chewed for
toothache as well as burned to repel insects (65).
Native to tropical America, sweet potato (I. batatas) is a perennial morning glory
vine that has been cultivated for over 5,000 years for its edible tubers in Mexico,
Central and lowland South America, and the West Indies. Today, sweet potato is
cultivated around the world, especially in developing countries (Plate 4). A decoc-
tion made from the leaves of this plant is used in folk remedies as a gargle to treat
mouth and throat tumors, and poultices are prepared for inflammatory tumors (64).
In Mexico, leaf decoctions are considered to be of “cold nature”, to reduce exces-
sive body heat, contemporarily defined as such illnesses as diarrhea, dysentery,
heart disease, stomach distress, fever, and gastrointestinal infection. In Chinese
traditional medicine, the tubers have been used as a medicinal herb to eliminate
secretion in perceived abnormal quantities of blood or other body fluids (79).

7.2. Biological Activities

Selected resin glycosides isolated from medicinal morning glory species have
recently been evaluated in several bioassays. In an effort to identify selective
antifungal agents, the inhibitory potential of the tricolorin and orizabin series was
evaluated on (1,3)-b-D-glucan synthase activity since the general structure of these
series resembles that of papaculacandins, which are potent in vitro and in vivo
inhibitors of this enzyme. Results showed that all the resin glycosides exhibited an
inhibitory activity (IC50 = 0.06–0.18 mg/mm3) comparable to that of papulacandin
B (IC50 = 0.100 mg/mm3) (115).
The cytotoxic potential of several resin glycosides has been evaluated against
mammalian cancer cultured cell lines. For tricolorin A (106), the most potent
cytotoxic activity (ED50 2.2 mg/cm3) was observed with human breast cancer and
>
Plate 4. Sweet potato. The roots of Ipomoea batatas, known in Mexico as “camote” (camohtli in
Nahuatl, edible root), is an important contribution to world nutrition in addition to have been used
by the native population as a “cold nature” remedy to reduce excessive body heat (A: The Latin
description in this illustration from the Badianus Manuscript reads Contra cordis calorem, “for
heat in the heart”; Libellus de Medicinalibus Indorum Herbis, 1552. Fol. 28v. CONACULTA-
INAH-MEX, with permission of the “Instituto Nacional de Antropologı́a e Historia”, Mexico).
Resin Glycosides from the Morning Glory Family 143

Plate 4. (continued) Aerial parts of commercially cultivated varieties are used to produce the crude
drug (B). The edible varieties derived from the wild Ipomoea tiliacea were cultivated by careful
selection by early native inhabitants of the tropical areas of the Americas (C: The varieties planted
in Mexico include those with white, yellow, orange, red and purple pulp and skin colors). Although
the sweet potato was introduced in Europe in early sixteenth century its importance was not
properly appreciated due a confusion perpetuated by herbals (D: In Gerald’s Herbal, an Andean
origin was ascertained to the sweet potato (Sisarum peruvianum) while claiming that the ordinary
potato originated in the English colony of Virginia (Battata virginiana) and calling them both
potato. Reproduced from reference (7) with permission of Dover Publications, Inc.)
144 R. Pereda-Miranda et al.

P-388 cells (55). All members of the tricolorin and orizabin series also exhibited a
weak cytotoxicity against colon carcinoma, squamous cell cervix carcinoma, and
ovarian cancer cell lines (ED50 4–20 mg/cm3), but a more potent effect was
observed when tested against oral epidermoid carcinoma (KB, ED50 1–5 mg/cm3).
The potency displayed for triacetylated orizabins, i.e., orizabins V–VII (69–71; KB,
ED50 7–10 mg/cm3), was greater than the values reported for the more polar isolates
with one or two acylating substituents (44, 45). Similar results were described for
the stansin series, which are composed of the same basic tetrasaccharide as the
orizabins (53), and they displayed moderate to marginal cytotoxic activity against
ovarian and cervical carcinoma cell lines (ED50 1.5–24 mg/cm3). All glycosidic
acids, i.e., tricoloric, tyrianthinic, and scammonic acids, were inactive against all
the cell lines tested, suggesting that the biological activity is associated with the
macrocyclic structure of these glycoresins (116).
The highly lipophilic arboresin, intrapilosin, murucin, murucoidin, and pesca-
prein series were found to be weakly cytotoxic or inactive in cytotoxicity assays,
e.g., murucoidin IV (162) exhibited marginal activity againts Hep-2 laryngeal
carcinoma cells (ED50 4 mg/cm3). The most potent of all resin glycosides is
ipomoeassin F that inhibits A2780 human ovarian cancer cell line with a value as
low as 0.37 mM (0.30 mg/cm3). The available data with the ipomoeassin series
suggest that minor variations in the peripherial oxygenation of the aglycone and
acylation pattern of the oligosaccharide core modulate the cytotoxicity of these
compounds to a significant extent (15, 16).
Quantitative antimicrobial assays against Staphylococcus aureus led to the
determination of a MIC (minimum inhibitory concentration) of 1.8 mg/cm3 for
tricolorin A (106). Tricolorin B (107) displayed a MIC of 8.7 mg/cm3 while the
values for the other tetrasaccharides of the tricolorin series were higher (MIC ¼ 40–
70 mg/cm3). A moderate activity was also recorded for all these compounds against
Mycobacterium tuberculosis (MIC ¼ 16–32 mg/cm3) (117). Convolvulaceous oli-
gosaccharides selected from the tricolorin, scammonin, orizabin, and murucoidin
series were evaluated for activity against a panel of Staphylococcus aureus strains
possessing specific efflux pumps (71, 118). The MIC values for most of the
amphipatic compounds ranged from 4 to 32 mg/cm3 against XU212 (possessing
the TetK multidrug efflux pump) and SA1199B (overexpressing the NorA multi-
drug efflux pump), compared with 64 and 0.25 mg/cm3, for tetracycline. This
activity was shown to be bactericidal. Two microbiologically inactive members
of the orizabin series, orizabins IX (72) and XIX (82), increased norfloxacin
susceptibility of strain SA1199B (118). Compound 72 at 25 mg/cm3 reversed
norfloxacin resistance fourfold (8 vs. 32 mg/cm3) for SA1199B, while 82 at
1 mg/cm3 completely inhibited SA1199B growth in the presence of norfloxacin
(2 mg/cm3). All of the murucoidins strongly potentiated the action of norfloxacin
against this NorA over-expressing strain (71). They exerted a potentiation effect
that increased the activity of norfloxacin by fourfold (8 mg/cm3 from 32 mg/cm3) at
concentrations of 5–25 mg/cm3; stoloniferin I (224) enhanced norfloxacin activity
eightfold when incorporated at a concentration of 5 mg/cm3. Orizabin IX (72) and
reserpine were nearly equipotent with respect to the inhibition of ethidum bromide
Resin Glycosides from the Morning Glory Family 145

efflux by SA1199B, which is a substrate for many multidrug efflux pumps,

including NorA of S. aureus (118). From these results, there seems to be a correla-
tion between lipophilicity and antibacterial activity where the more lipophilic
compounds displayed significantly more activity than their polar analogues. The
size of the lactone ring was not crucial for antibacterial activity. The amphipathic
properties of these compounds resulting from the acylation of some of the free
hydroxy groups of the oligosaccharide core and the lipophilic alkyl chains of their
aglycones would seem to be important in facilitating cellular uptake to its multidrug
resistance pump target. It is possible that non-polar compounds will not interact
with the membrane efflux pumps and those that are polar poorly penetrate mem-
branes. In relation to the alleviation of refractive infections caused by effluxing
staphylococci, the most important result from the standpoint of the potential use of
resin glycosides as therapeutic agents is in combining these plant non-cytotoxic
products with commercial antibiotics.
The formation of complex resin glycoside aggregates or micelles explains, in
part, the cytotoxicity of this class of glycolipids with the potential to induce
membrane perturbation provoking an imbalance of cellular homeostasis. The inter-
actions of selected members of the tricolorin series with Sf9 cell membranes of the
insect Spodoptera frugiperda were studied in an attempt to unravel the mechanism
of action of these compounds. Tricolorin A (106) and all compounds evaluated with
an intact macrolactone-type structures showed the ability to increase the membrane
permeability for both cations (K+ and Na+) and anions (Cl) in a dose-dependent
fashion, without any measurable delay, suggesting a membrane disruption induced
by the amphiphilic properties of these molecules (119). The mammoside and
merremoside series exhibited ionophoric activity against Na+, K+, and Ca2+ ions
in human erythrocyte membranes (24, 25, 120). The ion-transport activities were
completely lost by cleavage of the macrocyclic structure. A speculative model of
transmembrane channel formation based on the crystal structure of tricolorin A
(106) has been proposed to explain the interactions of the resin glycoside aggre-
gates with their target cell membranes (100).

7.3. Pharmacology and Toxicology

The purgative effect of resin glycosides is confined to the whole molecule, presum-
ably bound to the intact complex mixture of glycoconjugates, since their glycosidic
acids are inactive. Resin glycosides induce peristalsis in the small intestine result-
ing in water elimination and numerous bowel movements within 1–2 h even after
moderate dosages. It has been proposed that these compounds dissolve lecithin
from the epithelial cells of the intestine resulting in its irritation (2).
Since even low overdoses cause severe inflammation of the mucous membranes
of both the small intestine and the colon, the past medicinal importance of the
Convolvulaceous resin glycosides as purgative herbal drugs has now been sup-
planted by the introduction of alternative phytopharmaceuticals with less severe
146 R. Pereda-Miranda et al.

effects. Resin glycoside mixtures also display a saponin-like effect, as reported for a
38,000-fold dilution of jalapin, which caused a total hemolysis of human blood (2).
The effect of tricolorin A (106) on intestinal and arterial smooth muscle con-
tractility was evaluated. This compound elicited a concentration-dependent stimu-
lation of spontaneous contractions of the guinea pig ileum (EC50 ¼ 6.99 
1.08 mg/cm3) and a concentration-dependent vasorelaxation of the isolated intact
rat aorta (EC50 ¼ 4.63  1.1 mg/cm3). Both effects were completely abolished in
the absence of extracellular Ca2+. Verapamil (1 mM), a L-type voltage-dependent
Ca2+ channel blocker, significantly inhibited the contractile response produced by
tricolorin A (106) on the ileum, though it did not affect the vasodilatory actions.
These findings suggest that the contractions induced on the ileum are caused mainly
by an increase in Ca2+ permeability that occurs through L-type voltage-dependent
Ca2+ channels found in the cell membrane. It seems that the influx of Ca2+
through voltage-dependent Ca2+ channels does not participate prominently in the
vasorelaxant effect. This vascular relaxation was endothelium-dependent and sig-
nificantly decreased in the presence of nitric oxide synthase and soluble guanylate
cyclase inhibitors, and a NO scavenger. These results suggest that the vasodilata-
tion is mainly due to activation of the NO/cGMP pathway (121).
Merremosides B (13) and D (15) exhibited antiserotonergic activity in mice with
ED80 values of 10 mg/cm3 and 2 mg/cm3, (cf., promethazine, ED80 2 mg/cm3) (24).
Intraperitoneal administration to mice of tyrianthins VI (91), VIII (scammonin VI,
68), and IX (93) resulted in antidepressant activity. Also, the activities of tryanthi-
nic acids I (94) and II (95), and the macrolactones scammonins I (63) and II (64),
and tyrianthins VI (91), VIII (68), and IX (93) exhibited dose-dependent protective
effects against pentylenetetrazole-induced seizures. Tyrianthin VI (91) and scam-
monin II (64) produced relaxant effects on spontaneous contractions in the isolated
rat ileum. Finally, the administration of compounds 68 and 93–95 to mouse brain
slices induced increments in the release of GABA and glutamic acid (48).

7.4. Chemical Ecology

The morning glory heavenly blue (I. tricolor) was the first Convolvulaceous plant
material subjected to activity-guided fractionation to identify its allelopathic con-
stituents (55). The phytotoxicity was traced to the resin glycosides present in
CHCl3-soluble extracts. Further chromatographic analysis of this active fraction
by reversed-phase HPLC yielded tricolorin A (106) as the main constituent (63%).
Studies on the inhibition induced by the glycoside mixture on H+-ATPase indicated
that the activity was mainly caused by tricolorin A (106), for this compound
strongly inhibited radicle growth of Amaranthus leucocarpus and Echinochloa
crus-galli (IC50 12–36 mM). Polar extracts prepared from the sweet potato root
periderm also inhibited germination of several species but attempts to isolate the
phytotoxic principles were unsuccessful (122). The CHCl3 maceration of powdered
sweet potatoes also afforded a bioactive residue, which clearly showed a defined
Resin Glycosides from the Morning Glory Family 147

zone of phytotoxicity by means of a preliminary bioautographic TLC. Separation of

this toxic band by preparative TLC and further purification by reversed-phase
HPLC proved that the active constituents were a resin glycoside mixture with
simonin IV (185, 48%) as the major principle (IC50 50–90 mM) (123). Tricolorin
A (106) has also been shown to uncouple photophosphorylation in spinach chloro-
plasts and to inhibit electron transport in photosystem II and ATP-synthesis,
probably by interfering directly with the thylakoidal membrane and depending on
the macrolactone-type structure for activity (124). The extracts from leaves of
Caloncyction aculeatum, known in Chinese as “yue-guang-hua” (moonlight
flower), showed a promoting effect on the growth and yield of various crops,
such as yams, peanuts, beans, and wheat. The plant growth regulator was separated
into components 40 and 41 by HPLC (36). The wide range of antimicrobial activity
displayed by these compounds is an example of synergy between related compo-
nents occurring in the same medicinal crude drug extract, i.e., microbiologically
inactive components disabling a resistance mechanism and potentiating the antibi-
otic properties of the active substances (71, 118). Thus, morning glories may
elaborate an array of amphipathic mixtures of glycolipids to confer selective
advantages against microbial infections through a combination of several mecha-
nisms of action, e.g., cytotoxicity and modulation of multidrug resistance pumps.
Intoxication of livestock has been attributed to both the resin glycoside and
alkaloidal contents of several morning glories, providing evidence for their protec-
tive potential against vertebrate herbivores (2, 83).

Acknowledgements. The corresponding author would like to express his gratitude to both the
“Consejo Nacional de Ciencia y Tecnologı́a” and the “Dirección General de Asuntos del Personal
Académico” (UNAM) for their support of the chemical investigations of the morning glories used
in Mexican traditional medicine through a series of grants over the past decade.

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Author Index

A Anjaiah, V., 67
Abbaspour-Tehrani, K., 66 Anke, H., 54
Abdallah, MA., 47, 58, 64, 66, 68–70, Ankenbauer, RG., 54, 70
73, 74 Anthoni, U., 54
Abe, H., 75 Aranda, E., 150
Abergel, RJ., 74, 75 Arceneaux, JEL., 54, 60, 74
Acevedo, L., 153 Arnow, LE., 54
Achnine, L., 153 Atkin, CL., 54
Actis, LA., 63 Austin, DF., 149
Adachi, K., 63 Awaya, JD., 54
Adam, J., 71 Azelvandre, P., 66
Adapa, S., 53
Adkinson, RA., 73
Adler, I., 70 B
Adolphs, M., 54 Bachhawat, AK., 54
Agrawal, PK., 152 Baek, N-I., 148
Aguirre-Crespo, F., 149 Bah, M., 147, 148, 150, 153
Akedo, H., 153 Bakker, PAHM., 66, 75
Akiyama, T., 75 Balashova, TA., 72
Alakhov YuB., 72 Ballio, A., 54
Albrecht, AG., 75 Baraldo, K., 59
Albrecht, AM., 58 Barbeau, K., 54, 75
Albrecht-Gary, AM., 57 Barbier, M., 69
Algee, SE., 75 Barelmann, I., 54, 70
Allard, KA., 54 Barklay, R., 55
Alonso, D., 150 Barnes, C., 72
Alonso-Cortes, D., 150 Barnes, CC., 150
Amann, C., 54 Barnes, CL., 62, 63, 71
Amin, SA., 75 Barry CE, III., 58
Ams, DA., 54 Barry, SM., 55
Anaya, AL., 150 Basu, M., 58
Anderegg, G., 54 Bateman, A., 58
Ando, A., 68 Bates, G., 71

155
156 Author Index

Bauer, AM., 59 Bricard, L., 63, 70

Baysse, C., 67 Briskot, G., 56
Beaman, BL., 59 Brito-Arias, M., 152
Beaulieu, JB., 60 Browder, CC., 58, 64
Beck, W., 61, 71 Brown, C., 59
Bedorf, N., 64 Bruland, KW., 54, 70
Beiderbeck, H., 55, 55, 70 Bruner, SD., 58
Bellama, JM., 61 Bruyneel, B., 73
Beltrán, JP., 73 Budzikiewicz, H., 8, 54–56, 59–61, 63–74
Benson, BA., 62, 63 Bulen, WA., 57
Bentley, MD., 60 Bultreys, A., 56
Berge, O., 66 Burger, A., 64
Bergeron, RJ., 55, 75 Burgstahler, AW., 67
Bergquist, KE., 54 Burton, MO., 56
Bernardini, JJ., 74 Burton, PS., 55
Berner, I., 55 Butler, A., 54, 55, 61, 62, 65, 70, 74, 75
Bernhard, G., 67 Buyer, JS., 56
Bertholdt, H., 54 Buyer, JS., 69
Berti, AD., 55 Buzdar, MA., 73
Bertrand, S., 55 Bye, R., 148-150, 153
Bethuel, Y., 60 Byers, BR., 54, 57, 60, 65, 72, 74
Bezverbnaya, I., 66 Byrne, LT., 58
Bharti, N., 55
Bhattacharyya, S., 57
Bickel, H., 55 C
Bindereif, A., 73 Calis, I., 150
Bischoff, D., 55 Calugay, RJ., 57
Bishop, GG., 65 Candeloro, S., 57
Bister, B., 55 Cansier, A., 61
Blackburn, M., 57 Cao, S., 148
Blatzer, M., 73 Capon, RJ., 57
Blazhevich, OV., 65 Cardoso, A., 150
Bloom, ML., 74 Carilli, A., 54
Blunt, JW., 61 Carmeli, S., 57
Bock, K., 152 Carmi, R., 57
Boelaert, JR., 59 Carney, JR., 57
Boghozian, R., 71 Carpenter, KA., 150
Bohn, E., 56 Carrano, CJ., 2, 57, 61, 65, 69, 75
Bonner, DP., 65 Carrión, G., 148
Boopathi, E., 56 Carson, KC., 57, 58
Bössenkamp, A., 56 Carter-Franklin, JN., 65
Bosshardt, R., 55 Castañeda-Gómez, J., 77
Bouchara, JP., 55 Castelli, MV., 153
Boukhalfa, H., 56, 58, 64 Castignetti, D., 54
Boyer, GL., 62 Celia, H., 57, 60, 61
Brack, A., 71 Chai, W., 149
Braun, V., 56 Chain, EB., 54
Briat, JF., 75 Chakrabartty, PK., 57
Author Index 157

Chakraborty, RN., 58, 69, 71 D

Challis, GL., 55, 57 Dao, J., 54
Chambers, CE., 57 Dass, C., 152
Chari, VM., 150 Davis, WB., 54
Charkraborty, R., 72 de Graaf, FK., 73
Charlier, P., 68 de Hoffmann, E., 56
Chatfield, CH., 54 de Lorenzo, V., 56, 58
Chen, S., 149 De, M., 58
Chérigo, L., 149, 151 de Pauw, E., 68
Chi, Z., 73 De Vos, D., 66
Chiancone, E., 73 de Voss, JJ., 58
Chimiak, A., 67 Deér, A., 64, 74
Chı́rigo, L., 150 Degawa, M., 148
Choma, A., 71 Deguchi, T., 71
Christophersen, C., 54 Delfosse, P., 68
Cianciotto, NP., 54, 57, 65 Dell, A., 58, 68, 74
Ciche, TA., 57 Dellagi, A., 63
Cioci, G., 152 Delphosse, P., 63
Cobessi, D., 57 Demange, P., 57
Cockburn, BA., 59 Demange, P., 58, 68
Codd, R., 68 Deml, G., 58
Cody, YS., 57 DeMoll, E., 67
Colip, LA., 64 Deng, J., 58
Collinson, SK., 68 Dennis, JJ., 71
Collison, D., 70 Dertz, EA., 58
Colotti, G., 73 Derylo, M., 71
Cone, MC., 57 Desai, A., 71
Cook, JC Jr 58 Desai, SB., 57, 69
Cooper, RM., 66 Dhungana, S., 58, 64
Corbin, JL., 57 Di Vittorio, V., 54
Corey, EJ., 57 Diekmann, H., 58, 65
Cornelis, P., 56, 60, Diels, L., 58
65–67, 75 Diem, HG., 65
Cornish, AS., 57 Dilworth, MJ., 57, 58
Cortés, DA., 150 Dimise, EJ., 58
Cortés, JCG., 153 Ding, J., 151
Coulanges, V., 66 Dionis, JB., 55
Cox, CD., 54, 58, 70 Dioscorides 78
Cox, MM., 58 Dobernigg, B., 61
Coxon, B., 61 Dong, L., 58
Coyle, G., 70 Dönmez, AA., 150
Crawford, RL., 65, 74 Downer, DN., 54
Crosa, JH., 63, 75 Drake, SD., 67
Crueger, A., 65 Drechsel, H., 57–60, 67
Crumbliss, AL., 58, 61 du Moulinet d’Hardemare, A., 59
Crumrine, DS., 54 Du, XM., 148, 152
Cung, MT., 58 DuBois, JL., 54
158 Author Index

Dugave, C., 70 Fiedler, HP., 60, 66

Duus, JØ., 152 Filsak, G., 60
Duval, O., 55 Fisher, SM., 65
Dwek, RA., 152 Folschweiller, N., 57
Dyer, DW., 67 Fomichev YuK, 65
Forrester, JD., 74
Forsythe, JH., 54, 58, 61
E Foster, LA., 67
Ecker, DJ., 59 Fragoso-Serrano, M., 148, 150, 151, 153
Edwards, KJ., 62 Frampton, J., 147
Egawa, Y., 59, 63 Franzblau, S., 153
Ehlert, G., 59, 72 Frederick, CB., 60
Eich, E., 147 Frejd, T., 69
El Hage Chahine, JM., 59 Freund, S., 59, 71
Elliot, GT., 55 Fuchs, R., 56, 60, 64, 70-73
Elliot, T., 152 Fujii, K., 61
Emery, T., 59, 67, 70 Fujimoto, K., 149
Enard, C., 67 Fujita, E., 68
Engels, JW., 152 Fujita, T., 67
Eng-Wilmot, DL., 59, 62, 63 Fujita, Y., 74
Enriquez, RG., 150 Fukai, T., 67
Ensign, JB., 57 Fukasawa, K., 60
Ericson, TJ., 68 Fukuda, H., 151
Escalante, AM., 153 Fukuda, Y., 57
Escalante-S´nchez, E., 125, 127, 148, Fukunaga, T., 149
150, 151 Fürstner, A., 152, 153
Escobedo-Martı́nez, C., 149–151 Furukawa, J-I., 152
Esikova, TZ., 72 Furumai, T., 67
Essen, LO., 75 Fuse, H., 62
Estrada-Soto, S., 149, 150
Estrada-Soto, S., 150
Evans, R., 148
Ewing, DF., 55, 71 G
Ewing, M., 65, 69 Gabrik, AH., 60
Expert, D., 63, 67, 69, 75 Gademann, K., 60
Gallay, J., 61
Galles, JL., 63
F Garcı́a, A., 153
Faccheti, S., 152 Garcı́a-Valdéz, E., 67
Fadeev, EA., 65, 75 Gardan, L., 63
Fairlee, JM., 58 Gardenić, D., 57
Falk, KE., 69 Garlich, JR., 55
Fang, Y., 149, 151 Garner, BL., 60
Faulkner, DJ., 70 Gaspar, E., 151
Faull, KF., 62 Gaspar, EMM., 150
Feistner, G., 60 Gaudemer, A., 69
Fekete, FA., 60, 74 Gäumann, E., 55
Fernández, DU., 70 Gaymard, F., 75
Fetherston, JD., 67 Geisen, K., 60, 72
Author Index 159

Geoffroy, V., 54, 60, 63, 71–74 Guerrero, JA., 153

Georges, C., 66 Gunther, RT., 147
Georgias, H., 60 Guo, YT., 148, 152
Gerard, J., 147 Guo, Z-W., 152
Gerbig, DG. Jr., 67 Gupta, PC., 148
Geyer, A., 152 Gustin, D., 70
Gheysen, I., 56 Gutierrez, M., 150
Ghosh, A., 75 Guza, RC., 148
Ghosh, S., 54 Gwinner, T., 56
Gibbons, S., 149, 151, 153 Gwose, I., 60, 63, 68
Gibson, BW., 60, 67
Gibson, F., 60, 68
Giles, RGF., 58 H
Gilis, A., 60 Haag, H., 59, 60, 66
Gill, JH., 57 Haas, H., 73
Gill, PR. Jr., 69 Hagiwara, Y., 68
Gilmour, C., 65 Hagmann, L., 64
Gipp, S., 60 Hahn, FE., 61
Glenn, AR., 57, 58 Hahn, J., 60
Glenn, AR., 58 Hall, GE., 55
Glithero, A., 152 Hallé, F., 66
Glorius, M., 67 Hamada, Y., 58
Glowacki, Z., 67 Hammond, GB., 150
Gnecco, D., 150 Hanazono, H., 152
Gobin, J., 60 Hancock, DK., 61
Goldman, SJ., 69 Hantke, K., 55, 59, 61, 67
Gomila, M., 67 Hao, X., 151
Gondol, D., 71 Harada, K., 61, 67
Gonzalez, H., 150 Harayama, T., 75
Gore, M., 59 Harrington, JM., 61
Gore, MP., 57 Harris, WR., 61
Gotfredsen, CH., 152 Harrison, DA., 150
Goto, M., 60 Harrison, HF., 153
Gough, FJ., 57 Hartmann, R., 61, 70
Gougoutos, JZ., 65 Hasegawa, Y., 62
Gould, SJ., 57 Haselwandter, K., 61
Gracey, HE., 67 Hayase, Y., 64
Gräfe, U., 68 Hayashi, T., 71
Gram, L., 54 Haydon, AH., 54
Grayson, SL., 59 Hayen, H., 61
Grayson, SL., 63 Hayes, RN., 60
Green, DH., 75 Haygood, MG., 61, 65
Greenwald, J., 60 He, Y., 149
Griffiths, GL., 60 Heathcock, CH., 133, 135, 152
Gross, DC., 57 Heim, S., 70
Groves, JT., 65, 74, 75 Heine, HS., 64
Gruffaz, C., 60, 66, 67 Hennard, C., 70, 74
Gu, Q., 73, 151 Hernández, R., 153
160 Author Index

Hernández-Carlos, B., 148, 149 I

Herrera-Ruiz, M., 149, 150 Ibarra, C., 153
Hersman, LE., 23, 54, 58, 61, 64 Igarashi, Y., 67
Hess-Leisinger, K., 74 Iglesias-Prieto, R., 153
Heuer, H., 70 Iitaka, Y., 68, 72
Heymann, P., 67 Ikenishi, Y., 64
Hickford, SHJ., 61 Imberty, A., 152
Hidaka, S., 64 In, N., 148, 150
Hildebrand, U., 61 Ino, A., 62
Hill, KK., 64 Inoue, H., 62
Hirata, Y., 60 Ishida, K., 63
Hiratake, J., 68 Ishida, Y., 68
Hodgkin, DC., 57 Ishihara, K., 70
Hoegy, F., 61 Ishikawa, J., 67
Hoette, TM., 75 Ishimaru, CA., 62
Höfle, G., 65 Ishizuka, M., 63
Högberg, T., 67 Ito, T., 62
Hohlneicher, U., 61 Ito, Y., 59, 62, 63, 65
Hohnadel, D., 66 Iyer, S., 56, 64
Holden, I., 71
Holinsworth, B., 61
J
Holt, PD., 62, 65
Jackson, M., 67
Homann, VV., 62, 65
Jackson, RW., 66
Honda, F., 150
Jacobo-Herrera, N., 151
Hopkinson, BM., 62
Jacques, P., 63, 68
Horiuchi, Y., 149
Jalal, MAF., 62, 63, 73
Horwitz, MA., 60
Jeanjean, F., 153
Hoshino, Y., 67, 68
Jiang, ZH., 152
Hossain, MB., 62, 63, 72, 73
John, SG., 58
Hou, Z., 62
Johnson, MT., 58
Hough, E., 62
Johnsson, A., 67
Howard, DH., 62
Jones, AM., 63
Hsieh, LL., 60
Jones, RJ., 65
Hu, X., 62
Jordan, M., 57
Huáman, Z., 149
Jülich, M., 63
Huang, A., 61
Jung, G., 55, 57–61, 64, 66, 71
Huang, G., 55
Jung, HT., 65
Huang, H., 149
Jung, O., 59
Huang X-F, 151
Huber, P., 53
Hubschwerlen, C., 60 K
Hugi, A., 61 Kaatz, GW., 151, 153
Huguet-Termes, T., 147 Kachadourian, R., 63
Huhn, W., 64 Kaiser, D., 57
Hui Y-Z., 152 Kameyama, T., 63, 72
Hulcher, FH., 62, 68 Kamino, K., 63
Huschka, HG., 62, 64, 74 Kamnev, AA., 63
Hütter, R., 74 Kanoh, K., 57, 63
Author Index 161

Karahashi, A., 150 Kubo, I., 152

Kashporov, IA., 72 Kubo, K., 151
Kato, S., 67 Kulshreshtha, DK., 150, 151
Katsube, Y., 68 Kunesch, G., 59, 63
Kawaguchi, K., 62 Kunze, B., 65
Kawai, H., 67 Küpper, FC., 61, 75
Kawamura, Y., 64 Kurasawa, S., 63, 72
Kawanishi, H., 153 Kuwabata, K., 151
Kawasaki, T., 148–152 Kyslı́k, P., 70, 74
Kawashima, K., 148
Kawata, M., 149
Kazmaier, P., 151 L
Keating, TA., 69 Lacey, E., 57
Keller-Schierlein, W., 53, 55, 63–67, 74 Lack, JG., 58
Kennedy, JF., 152 Lalucat, J., 67
Kerley, EL., 59 Lancaster, JR. Jr., 59
Khan, MA., 60 Landreau, A., 55
Khanna, SN., 148 Lane, SJ., 65
Kieffer, B., 73 Langenheim, JH., 147
Kilz, S., 56, 64 Lankford, CE., 57, 65
Kindscher, K., 150 Lanzi, RA., 60
Kinghorn, AD., 150 Larcher, G., 55
Kingston, DGI., 148 Larson, DP., 133, 152
Kinkel, BA., 64 Laurent, J., 63
Kinn, J., 54 Laus, G., 65, 66
Kitagawa, I., 148, 150, 153 Lawlor, KM., 69
Kitahara, T., 74 Leary, JA., 72
Klein, MP., 69 Ledyard, KM., 65
Kline, SJ., 55 Lee, B., 67
Kloepper, JW., 64 Lee, BH., 65
Klumpp, C., 64 Lee, CH., 65
Ko, H., 60 Lefèvre, JF., 67, 72
Kobayashi, H., 149 Lehmann, CW., 152
Kobayashi, S., 64, 152 Leleo, G., 63
Köberle, M., 56 Lemenceau, P., 75
Koedam, N., 67 Lenz, C., 64
Koehl, P., 67 León, I., 150
Kogetsu, H., 149 Leong, J., 64, 72
Kohinata, K., 148 Leong, SA., 65, 69
Kohl, W., 64, 67 León-Rivera, I., 149, 150
Kokubo, S., 64, 72 Lesueur, D., 65
Komaki, H., 61, 68, 75 Leuenberger-Ryf, H., 62
Konetschny-Rapp, S., 55, 64, 66 Levy, E., 57
Kong L-Y., 149, 151 Lewis, BL., 62
Koppisch, AT., 58, 64 Lewis, CJ., 71
Korth, H., 60, 61, 64, 68, 72, 74 Lewis, TA., 65
Koshito, N., 152 Lex, J., 61, 71
Krezdorn, E., 58 Li, Y., 151
162 Author Index

Libman, J., 71 Manfredi, KP., 150

Liles, MR., 65 Mann, EL., 65
Linares, A., 148 Mannich, C., 148
Linares, E., 148, 150 Marahiel, MA., 75
Lindner, H., 73 Maraite, H., 56
Lindow, SE., 63 Marrone, BL., 64
Linget, C., 58 Marshall, BJ., 65, 69
Linke, WD., 65 Marshall, PS., 65
Lion, C., 59 Martin, JD., 61, 65
Little, JL., 71 Martinez, JL., 58
Liu, G., 73 Martinez, JS., 65, 74
Liu, J., 151 Martı́nez, S., 153
Liu, WC., 65 Masuda, K., 61
Live, DH., 54, 70 Mata, R., 150, 153
Livens, FR., 70 Matsubara, I., 71
Llinás, L., 65 Matsui, M., 74
Locher, HH., 60 Matsumoto, Y., 67
Lochhead, AG., 56 Matsunaga, T., 57
Loehr, TM., 69 Matsuoka, M., 67
Loghry, RA., 62 Matsuura, S., 74
Longcope, DC., 60 Matthijs, S., 22, 56, 65, 66
Loomis, LD., 65 Mattiasson, B., 69
Loper, JE., 62 Matzanke, B., 57
Lorence, A., 153 Maurer, B., 66
Loring, H., 150 Maurer, PJ., 66
Lorkiewicz, Z., 71 Maurice, PA., 54, 61
Lotina-Hennsen, B., 153 Mavridis, A., 60
Lotz, R., 59 May, JJ., 66
Love, SK., 63 McArdle, JV., 70
Lowman, DW., 71 McCoy-Simandle, K., 54
Lu, SF., 133, 152 McCullough, WG., 66
Luo J-G, 149 McDougall, S., 66
Luo, M., 65, 75 McDyer, D., 59
Luther, GWIII., 62 McGovern, KA., 55
Lysak, VV., 65 McIntyre, DD., 57
McManis, JS., 55, 75
McMurry, TJ., 60
M Mehrotra, M., 73
Mabbott, GA., 60, 74 Meiwes, J., 60, 64, 66
MacDonald, JC., 65 Melville, CR., 57
MacLeod, JK., 58, 151 Mendenhall, JV., 59
Madhusudan, KP., 150 Mentjox-Vervuurt, JM., 73
Madhusudanan, KP., 151 Mercado-Blanco, J., 66
Magos, G., 150 Mergeay, M., 60, 73
Magrath, DI., 60 Mergo, PJ., 59
Mahariel, MA., 66 Merkal, RS., 66
Majcherczyk, PA., 74 Mertens, P., 64
Maksimova, NP., 65 Mertz, C., 58
Author Index 163

Messenger, AJM., 66 Mullis, KB., 67

Metzger, J., 59 Munsch, P., 73
Meyer, B., 152 Münzinger, M., 56, 67
Meyer, JF., 66 Murabayashi, A., 62
Meyer, JM., 48, 52, 54–56, 58, 60, 63, Murakami, K., 62
65–74 Murakami, M., 62, 63
Michalczyk, R., 56 Murakami, Y., 67
Michalczyk, R., 58 Murata, H., 149, 151
Michalke, R., 56, 66 Mynott, R., 153
Miethke, M., 75
Mikami, Y., 61, 67, 68 N
Milewska, MJ., 67 Nabbut, NH., 65
Miller, JS., 148 Nader, M., 60
Miller, MC., 67 Naegeli, HU., 62, 67, 68
Miller, MJ., 58, 65, 66, 73, 75 Naganawa, H., 68, 72
Mirón-López, G., 149, 150 Nagano, T., 153
Mislin, GL., 61, 64, 74 Nagao, Y., 68, 75
Misra, AL., 85, 148 Nakagawa, T., 151
Mitchell, EP., 152 Nakai, H., 64
Mitscher, LA., 67 Nakajima, M., 67
Miyagishima, T., 63 Nakamura, H., 68, 72
Miyahara, K., 148–152 Nakatsu, T., 152
Miyanaga, S., 67 Navarrete-Vásquez, G., 150
Miyasaka, T., 68 Navarro, J., 80
Miyase, T., 148 Neilands, JB., 54, 56, 58, 60, 62, 65–69,
Miyoshi, S., 68 71, 73
Mocharla, R., 63 Nemoto, A., 68
Modi, M., 67, 70 Nemoto, K., 148
Modi, VV., 67, 70 Neu, MP., 58
Moe, AL., 64 Neu, P., 56
Mohn, G., 67 Neudörfl, J., 49
Molina-Salinas, GM., 150 Neuenhaus, W., 68
Moll, H., 67 Newkirk, JD., 68
Montanarella, L., 152 Nicholson, GJ., 55, 58, 61
Moore, CH., 60, 67 Nielsen, PH., 54
Moore, ERB., 70 Niesel, DW., 69
Moore, ML., 58 Nieto, DA., 150
Moore, RE., 67 Nishi, M., 148, 149, 152
Morel, FMM., 62 Nishio, T., 62
Moreno-Sánchez, R., 153 Nishio, T., 68
Mossialos, D., 67 Nishioka, H., 75
Mouck, M., 57 Nitoda, T., 62
Mukai, A., 67, 75 Niwa, M., 151
Mukoyama, D., 57 Noah, WH., 59
Mulet, M., 67 Noda, N., 148–152
Müller, A., 66, 67 Noguchi, H., 148
Müller, SI., 67 Nomizu, M., 152
Müller, T., 152 Norris, A., 148
164 Author Index

O Pereda-Miranda, R., 77, 125, 127, 147–153

Omura, S., 72, 73 Perez, F., 150
O’Brian, IG., 68 Pérez, S., 152
O’yang, Q., 152 Pérez-Ortı́n, JE., 73
Obata, T., 67 Perry, RD., 67
Ockels, W., 61, 68, 74 Perryman, DD., 59
Oda, J., 68 Persmark, M., 69
Oelrichs, PB., 151 Perumal, PT., 75
Ohashi, K., 148 Peters, WJ., 69
Ohashi, K., 153 Petersen, BO., 54
Ohfune, Y., 68 Peterson, JK., 153
Ohkubo, T., 148 Peterson, T., 68, 69
Okabe, H., 151, 152 Petrescu, AJ., 152
Okabe, M., 148 Peuckert, F., 75
Okada, S., 63 Pezzuto, JM., 150
Okami, Y., 63, 72 Phaff, HJ., 54
Okuda, T., 59 Phanstiel, O., 73
Okujo, N., 68, 74 Phanstiel O iv 55
Okuyama, D., 68 Piémont, Y., 58
Olsson, PE., 66 Pierre, JL., 59
Onaka, H., 67 Pittman, P., 69
Ong, SA., 68 Plowman, JE., 69
Ongena, M., 54, 63, 68 Poling, M., 62, 73
Ono, M., 148–152 Pollack, JR., 67, 69
Orsi, N., 73 Poole, K., 65, 70
Ortiz, A., 70 Poppe, K., 69
Ottem, D., 73 Pouteau-Thouvenot, M., 69
Oudega, B., 73 Powell, DR., 63
Ozaki, M., 64 Powell, MV., 57
Pramanik, A., 56
Prelog, V., 55, 64
P Principe, PA., 65
Page, WJ., 57, 68, 73
Prome, D., 70
Pakchung, AAH., 68
Prpic, JK., 72
Palleroni, NJ., 67
Pulverer, G., 60, 61, 68, 72, 74
Pandey, A., 56
Puzzuoli, FV., 150
Pao, YL., 152
Pape, L., 71
Parkin, S., 67 Q
Paszczynski, AJ., 65, 74 Quadri, LEN., 69
Patel, HN., 57, 68, 69
Patel, PV., 69
Pathak, AK., 152 R
Pattus, F., 57, 60, 69, 70 Räber, M., 54
Paul, P., 69 Rabsch, W., 61, 69
Payne, SM., 60, 69 Rafie, R., 62
Pedersen, K., 67 Raharinosy, V., 66
Peixotto, SS., 69 Rahman, A., 59
Peng, J., 149 Ramiandrasoa, F., 59, 70
Author Index 165

Rao, KK., 71 Ruggiero, CE., 58, 64

Rao, KS., 56 Rutter, K., 58
Rastetter, WH., 68
Ratledge, C., 55, 58, 65, 66, 69–70
Ratnayake, R., 57 S
Ravel, J., 75 Sachdev, K., 151
Raymon, J., 74 Said-Fernández, S., 150
Raymond, KN., 2, 57, 58, 60–62, 64, Saiki, I., 67
65, 69, 71, 75 Saito, M., 68, 74
Razon, P., 153 Saito, N., 67
Reeder, DJ., 60, 61 Sakagami, M., 148
Reeve, JR. Jr., 60 Sakairi, N., 152
Reeves, JB., 65 Sakakibara, Y., 68, 74
Regenhardt, D., 70 Sakakura, A., 70
Reichenbach, H., 65 Sakurai, H., 67
Reid, RR., 62 Salah-el-Din, ALM., 70
Reid, RT., 70 Saltman, P., 71
Reilly, SD., 56 Sanders-Loehr, J., 63, 69
Reimmann, C., 74 Sandy, M., 62, 75
Reissbrodt, R., 69, 70 Sanjeevaiah, P., 54
Rencurosi, A., 152 Sansinenea, E., 70
Renshaw, JC., 70 Sarg, B., 73
Renz, J., 71 Sasaki, K., 60
Reusser, P., 55 Sato, S., 60
Reynolds, WF., 150 Sattely, ES., 70, 74
Ribas, JC., 153 Saxena, B., 70
Ricca, CS., 65 Sayer, JM., 70
Richomme, P., 55 Schäfer, M., 56, 65–68, 70, 73
Rico-Gray, V., 148 Schaffner, EM., 70
Riggiero, CE., 64 Schalk, IJ., 57, 60, 61, 70, 74
Rinehart, KL. Jr., 55, 58, 70 Scheel, TA., 65
Rı́os, M., 150 Schlegel, K., 70, 71
Risse, D., 55, 70 Schmickler, H., 72
Rivero-Cruz, I., 153 Schmid, DG., 57
Robins-Browne, RM., 72 Schmidt, RR., 152
Robinson, JP., 70 Schneider, HA., 74
Robson, GD., 70 Schneider, K., 55
Rochel, N., 57 Schrettl, M., 73
Rodgers, D., 62 Schröder, H., 56, 63, 71
Rojas, A., 153 Schroeder, BG., 58
Römer, A., 68 Schroth, MN., 64
Romero, RB., 64 Schumann, P., 148
Rosas-Ramı́rez, D., 77, 150 Schwarting, G., 150
Ruangviryachai, C., 56, 70 Schwyn, B., 69, 71
Rudolph, K., 60 Seinsche, D., 63, 71, 72
Rue, EL., 54, 70 Seki, N., 74
Rüedi, P., 150 Sekiguchi, T., 63
166 Author Index

Serino, L., 73 Stoll, A., 71

Serratrice, G., 59 Stolowich, NJ., 55
Seto, H., 67 Storey, EP., 71
Sezgin, Y., 150 Stroech, K., 71
Shah, KS., 67 Strömpl, C., 70
Shah, S., 71 Stuart, SJ., 72
Shanzer, A., 71 Suenaga, K., 64, 72
Sharman, GJ., 71 Sultana, R., 72
Sharpless, B., 42, 136 Sulya, AW., 60
Sheeley, DM., 150 Sun, N-Y., 148, 152
Sheldon, RI., 67 Sun, WY., 64
Shelley, JT., 64 Sunderland, CJ., 62
Shibuya, H., 148, 153 Süssmuth, RD., 55
Shiman, R., 71 Suzuki, T., 57, 71
Shinkai, K., 153 Sykes, RB., 65
Shinoda, S., 68, 74
Shinohara, C., 64, 72
Shinose, M., 73 T
Shin-Ya, K., 67, 75 Tabata, N., 72, 73
Shioiri, T., 58 Taghavi, S., 58
Shirahata, K., 71 Tait, GH., 72
Shivaji, S., 66 Takagi, M., 75
Shive, W., 60 Takahashi, A., 63, 72
Shizuri, Y., 63 Takahashi, M., 74
Shoolery, JN., 71 Takahashi, N., 149
Shou, Y., 64 Takahashi, T., 151
Siddiqui, BS., 72 Takahashi, Y., 73
Sigel, SP., 60 Takeda, R., 64
Simpson, FB., 71 Takeuchi, T., 63, 72
Skorupska, A., 71 Takeuchi, Y., 75
Smalley, MK., 150 Takeyama, H., 57
Smith, MJ., 71 Takimura, O., 62
Smith, RE., 55 Takita, T., 68
Snow, GA., 69, 71, 74 Tanaka, K., 152
Soe, CZ., 68 Tanaka, N., 68
Sokol, PA., 57, 71 Tanaka, Y., 68
Sowden, FJ., 56 Tao, H., 151
Spiro, TG., 71 Tao, J., 68
Srivastava, R., 151 Tappe, R., 66, 72
Stahl, DC., 60 Taraz, K., 54–56, 59–61, 63, 66, 67, 69–74
Staley, AL., 54, 70 Tasdemir, D., 150
Steffan, B., 71 Taylor, N., 57
Steglich, W., 71 Taylor, RJ., 70
Stephan, D., 70 Tebo, BM., 62
Stephan, H., 59, 71 Tehrani, KA., 66
Sterner, O., 54 Teintze, M., 64, 72
Steward, M., 57 Telford, JR., 72
Stintzi, A., 58, 65, 66, 71 Temirov, YuV., 72
Author Index 167

Templeton, AS., 62 V
Templeton, DH., 74 Valdebenito, M., 55, 67
Tewari, JD., 85, 148 van de Woestyne, M., 73
Theriault, RJ., 67 van der Drift, KMGM., 66
Thieken, A., 57, 72 van der Helm, D., 59, 62, 63, 72, 73
Thomas, MG., 55 van der Lelie, D., 60
Thomas, MS., 72 van Dorsselaer, A., 70
Thomas-Oates, JE., 66 Van Houdt, R., 58
Thompson, B., 57 van Loon, LC., 66
Thonart, P., 63, 68 Van Roy, S., 58
Ticknor, LO., 64 Van Tiel-Menkveld, GJ., 73
Tilio, R., 152 Van, VT., 66
Timmermann, BN., 153 van Vyncht, G., 68
Timmis, KN., 70 Vandecasteele, FPJ., 74
Tincu, JA., 62 Vanderberg, LA., 58
Tindale, Ä., 73 Vásquez-Navarrete, L., 149
Tiwari, A., 62 Vergne, AF., 73
Toeplitz, BK., 65 Vero-Barcellona, L., 54
Toma, K., 75 Verstraete, W., 73
Tomada, H., 73 Verzili, D., 73
Tomita, K., 61 Vicent, M., 61
Tomita, M., 68 Villa, J., 150
Tomoda, H., 72 Villareal, ML., 150
Tonolo, A., 54 Villatoro-Vera, R., 153
Tordera, V., 73 Vinokurov, LM., 72
Torres, L., 73 Visca, P., 73
Toyokuni, T., 54 Vischer, E., 55
Trejo, WH., 65 Viswamitra, M., 57
Trick, CG., 54 Voges, K., 58
Trinci, APJ., 70 Volmer, DA., 61
Trowitzsch-Kienast, W., 65 von Tigerstrom, M., 68
Tsuji, K., 151, 152 Voser, W., 55
Tsuji, T., 64, 72 Voss, JA., 66, 73
Tunstad, LMG., 72 Voßen, W., 73
Vuelvas, A., 153

U W
Ueguchi, T., 149 Wagner, H., 148, 150, 151
Uemura, D., 64, 72 Walker, JR., 65
Umehara, K., 148 Wallner, A., 73
Umemura, S., 70 Walls, F., 150
Umezawa, H., 63, 68, 72 Walsby, AE., 55
Umino, K., 59, 63 Walser, A., 64
Upton, RJ., 65 Walsh, CT., 68, 70, 74, 75
Urı́a Fernández, D., 54, 56, 68, Walz, AJ., 73
70, 73 Wang, J-S., 149
168 Author Index

Wang, QX., 73 Wormald, MR., 152

Wang, SY., 61 Worth Estes, J., 147
Wang, W., 73 Wuest, WM., 74
Ward, A., 151
Warner, PJ., 73
Warren, RAJ., 69
X
Wasielewski, E., 73
Xin, B., 149
Wathelet, B., 56, 65
Xin, MG., 55
Wawrousek, EF., 70
Xu, G., 74
Wawszkiewicz, EJ., 74
Xu, J., 58, 71
Webb, EA., 62
Weber, M., 74
Weimar, WR., 55
Wells, JS. Jr., 65 Y
Wendenbaum, S., 58 Yamada, F., 152
Wendrich, TM., 66 Yamada, Y., 74
Wenzel, G., 150 Yamamoto, S., 68, 74, 75
Westervelt, P., 74 Yamaoka, Y., 62
Wettstein, A., 55 Yang, CR., 149, 151, 152
White, AJ., 71, 74 Yazawa, K., 61, 67, 68
White, CA., 152 Yin, Y., 151
White, VE., 61 Yin, Y-Q., 149, 151
Wickramaratne, DBM., 150 Ykokawa, Y., 150
Widboom, PF., 58 Yoda, S., 149
Wiebe, MG., 70 Yokokawa, Y., 148
Wiegand, J., 55 Yoshida, T., 68, 74
Wildermuth, MC., 63 Yoshikawa, M., 148, 150
Williams, DH., 71 Yoshikawa, Y., 75
Williams, PH., 73 Youard, ZA., 74
Wilson, MK., 74 Yu, B., 152
Wilson, SR., 70 Yu, M., 150
Winkelmann, G., 55, 57-59, 61, 62,
64–67, 71, 72, 74
Winkler, S., 61, 74 Z
Winkler, S., 74 Zacchino, SA., 153
Wirtz, C., 153 Zähner, H., 55, 59, 60, 64, 66–68, 74
Wisse, JH., 148 Zalkin, A., 74
Wolf, M., 71 Zamri, A., 47, 75
Wolf, U., 67 Zawadzka, AM., 74
Wolter, MA., 152 Zhang, G., 54, 61
Wong, DK., 60 Zhang, GP., 65
Wong-Lun-Sang, S., 74 Zhao, L., 149
Woodruff, HB., 73 Zhu, W., 151
Subject Index

A Anachelins, 10, 24, 41

Acetyldimerum acid, 15 Anachelin H, synthesis, 42, 43
Acetylfusarinines, 13 Angiococcus disciformis,
Achromobactin, 33 myxochelin, 24
Acinetobacter baumannii, acinetobactin, 38 Anguibactin, 37–39
Acinetobacter haemolyticus, Anhydromevalonyl residues, 15
acinetoferrin, 31 Anthrachelin, 33
Acinetobactin, 38, 39 Antitumor activity, lysinol, 24
Acinetoferrin, 31 Aquachelins, 22
Actinomadura madurae, 11 photolytic degradation, 23
Actinomycetal metabolites, 11 Arboresinic acid, 101
Aerobacter (Enterobacter) aerogenes, Arthrobacter spp., arthrobactin, 30
aerobactin, 31 Arthrobacter terregens, arthrobactin, 30
Aerobactin, 31 Arthrobactin, 30
Aeromonas hydrophila, amonabactins, 18 Asperochrome, 14
Aeruginoic acid, 35 Asterobactin, 11
Agrobacterium tumefaciens, agrobactin, 25 Awaitins, 31
Agrobactin, 25 Azomonas spp., siderophores, 9
Alcaligenes denitrificans, alcaligin, 26 Azospirillum brasilense, spirilobactin, 17
Alcaligenes eutrophus, alkaligin E, 27 Azotobacter spp., siderophores, 9
Alcaligins, 26 Azotobacter vinelandii, protochelin, 24
Alcaligin E 27 Azotobactin, 5, 9, 24
Alterobactin, 18 Azotochelin (bis-DHB lysine), 24
synthesis, 42, 43 Azoverdin, 9
Alteromonas haloplanktis, bisucaberin, 26 Azurochelin, 35
Alteromonas luteoviolacea, alterobactin, 18
Amamistatins, 20
Aminochelin (mono-DHB cadaverine), 24 B
Amnesic shellfish poisoning (ASP), domoic Bacillibactin, 17, 54
acid, 39 Bacillus anthracis, petrobactin, 33
Amonabactins, 18 Bacillus megaterium, schizokinen, 30
Amphibactins, 22 Bacillus subtilis, enterobactin/corynebactin
Amphiphilic marine siderophores, 22 (bacillibactin), 54

169
170 Subject Index

Bacterium fluorescens liquefaciens Convolvulus spp., 79

(Pseudomonas fluorescens), 47 Convolvulus arvensis, 81
Batatin I, MS/MS ESI/NMR, 125–128 Convolvulus microphyllus, medicinal
Batatinosides, 91, 109, 123 use, 140
Batatosides, 109 microphyllic acid, 104
Battata virginiana, 143 Convolvulus scammonia, 81, 95
Beach morning glory, 109, 140 scammonin, 98
Bisucaberin, 26 Convolvulus sepium, 81
Bordetella spp., alcaligin, 26 Coprogens, 13, 15
Bradyrhizobium spp., ferric citrate, 29 Corrugatin, 21
Brazilian-grown jalap Corynebacterium glutamicum,
(Ipomoea operculata), 81 corynebactin, 17
Burkholderia cepacia (Pseudomonas Corynebactin, 17, 54
cepacia), cepabactin, 37 Crypthophilic acids, 98
cepaciachelin, 24 Cus-1/Cus-2, 85
ornibactins, 19 Cuscuta spp., 79
salicylic acid/azurochelin, 35 Cuscuta australis, 86
Cuscuta chinensis, 84, 88, 97
medicinal use, 140
C Cuscuta japonica, medicinal use, 140
Cacamotli tlanoquiloni, 81 Cuscutic acids, 86, 87, 97
Calonyctins, 91 Cuscutic resinoside A, 84
Calonyctin A1, computer Cyclodepsipeptide, 18
simulation, 131
Calonyction aculeatum, 91
Calystegia soldanella, 79, 81 D
medicinal use, 140 Des(diserylglycyl)ferrirhodin, 13
soldanelline, 99, 115 Desferri-ferrithiocin, 37, 38
Camote, 142 Desferrimaduraferrin, 11
5-Carboxy-5-hydroxy-2-oxoproline, 32 Desferrioxamines, 4, 27
Carboxymycobactins, 11, 20, 21 Diaminoalkanes, siderophores, 23
Catecholates, siderophores, 3, 16, 24 Dichrosides, 102
Cazahuate, 140–142 Digitatajalapin, 109
Cepabactin, 37, 38 Dihydroaeruginoic acid, 47
Cepaciachelin, 20, 24 2,3-Dihydroxybenzoic acid (DHB), 16
Chelators, 3 Dimerum acid, 15
Chondria armata, domoic acid, 39 Domoic acid, 39, 40
Chryseomonas luteola, chrysobactin/
chrysomonin, 18
Chrysobactin, 17, 33 E
Chrysomonin, 18 Enterobacter cloacae, aerobactin, 31
Citrate siderophores, 29 Enterobactin (enterochelin), 16, 17, 54
Citric acid, 29 Erwinia amylovora, 28
Clavariadelphus pistillaris, pistillarin, 24 Erwinia chrysanthemi, achromobactin, 33
Cloacin DF13 31 Erwinia rhapontici, proferrorosamine A
Convolvulaceae, 78 (pyrimine), 40
Convolvulin, 83 Escherichia coli, yersiniabactin, 36
Convolvulinolic acids, 84, 91 Exochelins, 12, 20
Subject Index 171

F I
Fe2+ binding ligands, 41 Indian jalap, 82
Fe3+, siderophores, 2 Intrapilosins, 109, 123
Ferri-alcaligin, 28 Ipomoea spp., 79
Ferribactins, 5, 9 Ipomoea arborescens, arboresinic acid, 101
Ferric citrate, 29 murucinic acid, 105
Ferric oxide hydrates, 2 batatinosides, 91, 109, 118, 119
Ferrichromes, 13, 14 batatins, 117–119
Ferrichrysin, 14 batatosides, 109, 113
Ferricrocin, 14 medicinal use, 142, 143
Ferri-enterobactin, 17 simonic acids, 111, 117, 118
Ferrioxamine, 28 simonin, 91, 113
Ferripyochelin I, 36 Ipomoea batatas, 91, 94, 111, 117,
Ferripyoverdins, 7, 9 119, 142
Ferrirhodin, 14 Ipomoea dichroa, dichrosides, 102
Ferrirubin, 14 Ipomoea digitata, digitatajalapin, 109
Ferri-siderophores, 2 Ipomoea hederacea, medicinal use, 140
Ferri-yersiniabactin, 38 Ipomoea intrapilosa, intrapilosins, 109
Ferroverdins, 41 medicinal use, 142
Fluopsin, 40 Ipomoea jalapa, 79, 81
Fluvibactin, 25 Ipomoea leptophylla, leptophyllins, 109
synthesis, 45 medicinal use, 140
Formobactin, 20 Ipomoea lonchopylla, lonchophyllic acid,
Fusarinines, 13, 15 116
Fusarium dimerum, dimerum Ipomoea mammosa (Merremia mammosa),
acid, 15 88, 103
Fuscachelins, 19 mammosides, 109
medicinal use, 140
Ipomoea multifida (Quamoclit multifida),
G multifidinic acids, 104
Ga3+, 3 Ipomoea muricata, muricatic acids, 91
Glycoresins, 79 Ipomoea murucoides, 90, 93
medicinal use, 140
murucinic acid, 105
H murucoidins, 109, 114
Halomonas spp., loihichelins, 22 Ipomoea nil (Pharbitis nil), medicinal use,
Halomonas aquamarina, aquachelins, 22 140
Heavenly blue (Ipomoea tricolor) 78, 86, pharbitic acid, 110, 117
100, 121 Ipomoea operculata 81, 88, 90, 93
Heterobactins, 19, 54 operculinic acids, 108, 116
Hydroxamates, siderophores, 3 operculins, 109
fungal L-ornithine-based, 12 Ipomoea orizabensis 81, 82, 94
Hydroxamic acid siderophores, 26, 39 medicinal use, 140
a-Hydroxy carboxylates, 3 scammonic acid, 97
8-Hydroxy-4-methoxymonothioquinaldic Ipomoea pes-caprae (railroad vine/beach
acid (thioquinolobactin), 39 morning glory), 90, 98
(11S)-Hydroxyhexadecanoic acid, 83 medicinal use, 140
172 Subject Index

Ipomoea pes-caprae var. brasiliensis, Lonchophyllic acid, 116

pescaprosides, 109 Lysinol, 24
Ipomoea purga, jalap, 80, 81
purgic acid, 117
Ipomoea purpurea, 93 M
Ipomoea quamoclit (Quamoclit pennata), Madurastatin, 11
quamoclin, 109 Malonichrome, 14
quamoclinic acid, 111 Mammosides, 109
Ipomoea squamosa, 84 Mammoside I (operculinic acid C), 88
Ipomoea stans, 81, 98 Marinobacter spp., marinobactins, 22
medicinal use, 140 vibrioferrin, 32
Ipomoea stolonifera, 90 Marinobacter hydrocarbonoclasticus,
stoloniferins, 109 petrobactin, 33
Ipomoea tricolor (Ipomoea violacea), Marinobactins, 22
78, 86 Maruba-asagao, 93
tricoloric acids, 100, 121 Marubajalapins, 93
tricolorins, 121 Merremia spp., 79
Ipomoea tiliacea, 143 Merremia hungaiensis, merremin, 120
Ipomoea tuberosa (Merremia tuberosa), tuguajalapins, 109, 120
woodrosins, 115 “Tu Gua”, 140
Ipomoea turbinata (Ipomoea muricata), Merremia mammosa, merremosides,
muricatin, 85 88, 103
medicinal use, 140 Merremosides, 88, 103
Ipomoea turpethum, 82 antiserotonergic activity, 146
turpethinic acids, 101 N-Methyl-N-phenylacetylhydroxylamine,
Ipomoea tyrianthina, scammonic acid, 97 40
Ipomoeassins, 84, 131 N-Methyl-N-thioformylhydroxylamine,
Ipomoeassin E, 135 40
synthesis, 135 Mexican scammony root/false jalap
Ipurolic acid (pharbitic acid C), 110, 116 (Ipomoea orizabensis), scammonic
Iron, 2 acid, 97
starvation, 3 Micacocidin, 36
Isopyoverdins, 5, 9 Microphyllic acid, 104
Isotriornicin (neocoprogen I), 15 Morning glories, arborescent, 140, 141
family, 79
Multifidinic acids, 104
J
Multifidins, 105
Jalap (Rhizoma Jalapae), 80, 81
Muricatic acids, 91
Jalapin, 83
Muricatin B, 85
Jalapinolic acid, 83, 85, 88
Murucinic acid, 105
Murucins, 106
L Murucoidins, 90, 93, 109,
Laxative properties, 83 123
Legiobactin, 34 norfloxacin, 144
Legionella pneumophila, legiobactin, 34, 48 Mycobacterium smegmatis,
Leptophyllins, 109 mycobactin S, 21
Lipopeptidic siderophores, 19 Mycobactins, 20, 21
Loihichelins, 22 Myxochelin, 24
Subject Index 173

N Pre-acinetobactin, 38, 39
Nahuatl, 140, 142, 143 Pre-pseudomonine, 38, 39
Nannochelin A, synthesis, 45, 46 Proferrioxamines, 26, 27
Nannochelin C, 31 Proferrorosamine A (pyrimine), 40
Nannocystis exedens, nannochelin C, 31 Protochelin, 24
Neocoprogen, 15 Pseudoalterobactins, 18, 19
Neuro-phycotoxin, domoic acid, 39 Pseudoalteromonas spp., 19
Neurospora crassa, 14, 16 Pseudobactins, 4
Neurosporin, 12 Pseudomonas spp., ferric citrate, 29
Nilic acid, 84, 88, 91, 97 micacocidin, 37
Nocardia spp., 20 pyoverdins, 4, 6, 49
Nocardia asteroides, 11 Pseudomonas aeruginosa, aeruginoic
Nocardia tenerifensis, heterobactin, 54 acid, 35
Nocardia transvalensis, transvalencin, 21 Pseudomonas corrugata, corrugatin, 21
Nocobactins, 20 Pseudomonas fluorescens, 8-hydroxy-
Nonomuraea pusilla, myxochelin, 24 4-methoxymonothioquinaldic acid
Nonproteinogenic amino acids (NPAAs), 4 (thioquinolobactin), 38
4,5-dihydroaeruginoic acid, 35
pseudomonine, 39
O quinaldic acid (quinolobactin), 39
Ochrobactins, 31
Pseudomonas GH, proferrorosamine
Ochrobactrum sp., ochrobactins, 31
A (pyrimine), 41
Operculina spp., 79
Pseudomonas mendocina, siderophores,
Operculinic acids, 90, 92, 93, 108, 120
23, 48
Operculins, 90, 109
Pseudomonas mildenbergii, N-methyl-
Orizabic acid, 94, 95
N-phenylacetylhydroxylamine, 40
Orizabins, 82, 94, 97, 123
Pseudomonas putida, pyridine-2,6-di
biological activities, 142
(monothiocarboxylic acid), 38
Ornibactins, 19
Pseudomonas roseus fluorescens,
Ornicorrugatin, 22
proferrorosamine A (pyrimine), 40
Pseudomonas stutzeri, amonabactins, 18
P pyridine-2,6-di(monothiocarboxylic
Palmitoylcoprogen, 15, 16 acid), 38
Palo bobo, 142 Pseudomonas syringae, achromobactin, 33
Papaculacandins, 142 yersiniabactin, 36
Parabactin, 25, 31, 44 Pseudomonine, 39, 40
synthesis, 44, 45 Pseudo-nitzschia spp., domoic acid, 39
Paracoccus denitrificans, parabactin, 25 Purgative action, morning glories, 79, 138,
Penicillium bilaii, pistillarin, 24 140, 145
Peptide siderophores, 4 Purging bindweed, 81
Pescaprein, 109, 123 Putrebactin, 26
Pescaprosides, 97, 109 Pyochelin, 35, 46
Petrobactin, 33 synthesis, 46
Pharbitic acids, 110, 117 Pyoverdins, 4, 47, 48ff
Photobactin, 24, 25 Pseudomonas spp., 4
Photolytic degradation, 22 Pyridine-2,6-di(monothiocarboxylic acid),
Photorhabdus luminescens, photobactin, 24 38, 39
Pistillarin, 12, 24 Pyrimine, 40
174 Subject Index

Q Scrophularia crypthophila, crypthophilic

Quahutzehuatl, 141 acids, 98
Quamoclin, 109 Serratia marcescens, serratiochelin, 24
Quinaldic acid (quinolobactin), 38 Serratiochelin, 24, 25
Shewanella putrefaciens, putrebactin, 26
Shuttle mechanism, 2, 8
R Siderochelin, 40
Ralstonia eutropha (Cupriavidus Siderochrome II, 24
metallidurans), 32 Sideromycins, 3
Ralstonia pickettii, (S,S)-(enantio)- Siderophores, 2
rhizoferrin, 34 catecholate, 16, 24
Ralstonia solanacearum, schizokinen, 30 catecholate units, 33
Ramaria spp., pistillarin, 24 citric acid units, 34
Resin glycosides, 83 cyanobacteria, 10
cytotoxicity, 142 diamino-/triaminoalkanes, 23
isolation, 123 hydroxamic acid, 12, 26
molecular modeling, 130 hydroxamic acid units, 30
purgative action, 79, 138, 140, 145 lipopeptidic, 19
structure elucidation, 123 marine siderophores, 22
synthesis, 131 2-oxoglutaric acid units, 32
Rhizobactin, 23, 31 peptides, 4
Rhizobium leguminosarum, schizokinen, 30 secondary, 2
Rhizobium meliloti, rhizobactin, 23, 31 Simonic acids, 109, 111
Rhizoferrins, 12, 34 Simonin I, 91
Rhizoma Jalapae, 80, 81 Sisarum peruvianum, 143
Rhizopus microsporus, (R,R)-rhizoferrin, 34 Skammonia, 78
Rhodobactin, 19 Soldanellic acid, 99, 115
Rhodococcus erythropolis, Soldanelline, 99, 115
heterobactins, 19 Spirilobactin, 17
Rhodococcus rhodochrous, 19 Staphylococcus hyicus, staphyloferrin, 32
Rhodotorula pilimanae, 15 Staphyloferrin, 30–34
Rhodotorulic acid, 15 Stoloniferins, 90, 109
Rhubarb of the Indies, 81 Stoloniferin I, norfloxacin, 144
Riñonina, 109 Streptoalloteichus sp., siderochelin, 40
Root of Michoacan, 79, 81 Streptomyces antibioticus, desferri-
ferrithiocin, 37
Streptomyces murayamaensis, ferroverdin,
S 41
Sake colorant A, 14 Succinyl-N1,3S-dihydroxyputrescine, 26
Salicylic acid, 35 Synechobactins, 10, 31
Salmochelin S4, 17 Synechococcus spp., synechobactins, 31
Salmonella typhimurium, hydroxamate
siderophore, 12
Scammonic acid, 95–99 T
Scammonins, 95, 146 Taxi mechanism, 2
Scammony, 79 Terregens factor, 31
Schizokinen, 10, 14, 30 Tetraglycylferrichrome, 13
Subject Index 175

Thermobifida fusca, fuscachelins, 19 U

Thioformin, 40 Ustilago sphaerogena, 14
Thioquinaldic acid, 38
Thioquinolobactin, 38
V
Transferrins, 2
Vibrio spp., amphibactins, 22
Transmembrane transport, 2
Vibrio anguillarum, anguibactin, 37
Transvalencin, 21
Vibrio cholerae, vibriobactin, 26
Triacetylfusigen, 13
Vibrio fluvialis, fluvibactin, 25, 26
Triaminoalkanes, siderophores, 23
Vibrio vulnificus, vulnibactin, 26
Tricatecholate siderophore, 24
Vibriobactin, 26
Tricoloric acids, 86, 100, 121
Vibrioferrin, 30–32
Tricolorins, 100, 121, 123, 128
Vicibactin, 12
Tricolorin A, 131
p-Vinylphenyl-3-nitroso-4-
biological activities, 142
hydroxybenzoate, 41
phytotoxicity, 146
Vulnibactin, 26
smooth muscle contractility, 146
synthesis, 131
unit cell, 128 W
Tricolorin G, 131 Woodrosin I, 131, 138
Triornicin (isoneocoprogen I), 15 synthesis, 138
Trojan Horse strategies, sideromycins Woodrosinic acid, 115
3, 49
Tuguajalapins, 109
Turpethinic acids, 101 Y
Tyrianthinic acids, 97, 146 Yersinia spp., yersiniabactin, 36, 37
Tyrianthins, 97, 146 Yersiniophore, 36, 37