Chembiomolecular Science At the Frontier of Chemistry and

Biology

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Preface

To understand biological functions at the molecular level and create new pharma-
ceuticals that can contribute to improving human health, the integration of both
chemical and biological approaches is indispensable. Chemical biology, taking
advantage of the creativity of chemistry to explore biology, is currently a very
important stream in life science. Here we propose “chembiomolecular science” as a
further advancement in the field of life science through the integration of chemical
biology with molecular-level biological studies. Chembiomolecular science will
facilitate the elucidation of new biological mechanisms as potential drug targets and
will enhance the creation of new drug leads. This new field will promote world-
class life science research in Japan to the international scientific community.
In 2009, the Uehara Memorial Foundation announced a 3-year research program
focused on chembiomolecular science. To date, 20 research groups in Japan have
been funded under this program. The aim of the symposium was to bring together
leading scientists in the field of chembiomolecular science to discuss their latest
research. The main topics to be addressed in the symposium were:
1. Chembiomolecular chemistry
2. Chembiomolecular biology
3. Chembiomolecular medicinal chemistry
The explicit aims of this symposium were to contribute to understanding the funda-
mentals of life science based on chemical and biological approaches, and the devel-
opment of novel strategies for discovering new drug leads.
We are very pleased to be able to publish the proceedings of this exciting
symposium.

Tokyo, Japan Masakatsu Shibasaki

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Contents

Part I Chembiomolecular Chemistry

Chemistry of Mycolactones, the Causative Toxins

of Buruli Ulcer ................................................................................................. 3
Yoshito Kishi
Practical Synthesis of Tamiflu and Beyond .................................................. 15
Motomu Kanai
An Approach Toward Identification of Target Proteins
of Maitotoxin Based on Organic Synthesis ................................................... 23
Tohru Oishi, Keiichi Konoki, Rie Tamate, Kohei Torikai,
Futoshi Hasegawa, Takeharu Nakashima, Nobuaki Matsumori,
and Michio Murata
Inhibitors of Fatty Acid Amide Hydrolase ................................................... 37
Dale L. Boger
Small Molecule Tools for Cell Biology and Cell Therapy ........................... 51
Motonari Uesugi
Toward the Discovery of Small Molecules Affecting
RNA Function.................................................................................................. 59
Shiori Umemoto, Changfeng Hong, Jinhua Zhang, Takeo Fukuzumi,
Asako Murata, Masaki Hagihara, and Kazuhiko Nakatani
New Insights from a Focused Library Approach
Aiming at Development of Inhibitors of Dual-Specificity
Protein Phosphatases ...................................................................................... 69
Go Hirai, Ayako Tsuchiya, and Mikiko Sodeoka
The Deep Oceans as a Source for New Treatments for Cancer .................. 83
William Fenical, James J. La Clair, Chambers C. Hughes,
Paul R. Jensen, Susana P. Gaudêncio, and John B. MacMillan

vii
viii Contents

Search for New Medicinal Seeds from Marine Organisms ......................... 93

Motomasa Kobayashi, Naoyuki Kotoku, and Masayoshi Arai
Identification of Protein–Small Molecule Interactions
by Chemical Array.......................................................................................... 103
Hiroyuki Osada and Siro Simizu

Part II Chembiomolecular Biology

Small Molecule-Induced Proximity ............................................................... 115

Fu-Sen Liang and Gerald R. Crabtree
High-Throughput Screening for Small Molecule
Modulators of FGFR2-IIIb Pre-mRNA Splicing ......................................... 127
Erik S. Anderson, Peter Stoilov, Robert Damoiseaux,
and Douglas L. Black
Identification of Signaling Pathways That Mediate Dietary
Restriction-Induced Longevity in Caenorhabditis elegans .......................... 139
Masaharu Uno, Sakiko Honjoh, and Eisuke Nishida
Roles for the Stress-Responsive Kinases ASK1
and ASK2 in Tumorigenesis ........................................................................... 145
Miki Kamiyama, Takehiro Sato, Kohsuke Takeda, and Hidenori Ichijo
Tailored Synthetic Surfaces to Control Human Pluripotent
Stem Cell Self-Renewal................................................................................... 155
Laura L. Kiessling
Cell-Surface Glycoconjugates Controlling Human
T-Lymphocyte Homing: Implications for Bronchial
Asthma and Atopic Dermatitis ...................................................................... 167
Reiji Kannagi, Keiichiro Sakuma, and Katsuyuki Ohmori
Establishment of a Novel System for Studying
the Syk Function in B Cells ............................................................................ 177
Tomohiro Kurosaki and Clifford A. Lowell
Visual Screening for the Natural Compounds
That Affect the Formation of Nuclear Structures ......................................... 183
Kaya Shigaki, Kazuaki Tokunaga, Yuki Mihara, Yota Matsuo,
Yamato Kojimoto, Hiroaki Yagi, Masayuki Igarashi, and Tokio Tani
Versatile Orphan Nuclear Receptor NR4A2 as a Promising
Molecular Target for Multiple Sclerosis and Other
Autoimmune Diseases ..................................................................................... 193
Shinji Oki, Benjamin J.E. Raveney, Yoshimitsu Doi,
and Takashi Yamamura
Contents ix

Antiviral MicroRNA ....................................................................................... 201

Ryota Ouda and Takashi Fujita
Synaptic Function Monitored Using
Chemobiomolecular Indicators ..................................................................... 207
Masamitsu Iino

Part III Chembiomolecular Medicinal Chemistry

Practical Catalytic Asymmetric Synthesis of a Promising

Drug Candidate ............................................................................................... 219
Masakatsu Shibasaki
Hunting the Targets of Natural Product-Inspired Compounds.................. 229
Slava Ziegler and Herbert Waldmann
Chemical Approaches for Understanding and Controlling
Infectious Diseases .......................................................................................... 239
Hirokazu Arimoto
Nongenomic Mechanism-Mediated Renal Fibrosis-Decreasing
Activity of a Series of PPAR-g Agonists ........................................................ 249
Hiroyuki Miyachi
Novel Carbohydrate-Based Inhibitors That Target
Influenza A Virus Sialidase ............................................................................ 261
Mark von Itzstein
Multidrug Efflux Pumps and Development of Therapeutic
Strategies to Control Infectious Diseases ...................................................... 269
Kunihiko Nishino
Enzymes as Chemotherapeutic Agents ......................................................... 281
Ronald T. Raines
Mechanism of Action of New Antiinfectious Agents
from Microorganisms ..................................................................................... 293
Nobuhiro Koyama and Hiroshi Tomoda
Correction of RNA Splicing with Antisense Oligonucleotides
as a Therapeutic Strategy for a Neurodegenerative Disease ....................... 301
Yimin Hua, Kentaro Sahashi, Frank Rigo, Gene Hung, C. Frank Bennett,
and Adrian R. Krainer
Modulation of Pre-mRNA Splicing Patterns with Synthetic
Chemicals and Their Clinical Applications .................................................. 315
Masatoshi Hagiwara
Index ................................................................................................................. 321
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Contributors

Erik S. Anderson Molecular Biology Institute, University of California, Los Angeles,

CA, USA
The David Geffen School of Medicine, University of California, Los Angeles,
CA, USA
Masayoshi Arai Graduate School of Pharmaceutical Sciences, Osaka University,
Osaka, Japan
Hirokazu Arimoto Graduate School of Life Sciences, Tohoku University,
Sendai, Japan
C. Frank Bennett Isis Pharmaceuticals, Carlsbad, CA, USA
Douglas L. Black Howard Hughes Medical Institute, University of California,
Los Angeles, CA, USA
Department of Microbiology, Immunology and Molecular Genetics, University
of California, Los Angeles, CA, USA
Dale L. Boger Department of Chemistry, The Scripps Research Institute,
La Jolla, CA, USA
Gerald R. Crabtree Howard Hughes Medical Institute, Stanford University
School of Medicine, Stanford, CA, USA
Robert Damoiseaux Molecular Screening Shared Resource, University of
California, Los Angeles, CA, USA
Yoshimitsu Doi Department of Immunology, National Institute of Neuroscience,
National Center of Neurology and Psychiatry, Tokyo, Japan
William Fenical Center for Marine Biotechnology and Biomedicine, Scripps
Institution of Oceanography, University of California, San Diego, La Jolla, CA, USA

xi
xii Contributors

Takashi Fujita Laboratory of Molecular Genetics, Institute for Virus Research,

Kyoto University, Kyoto, Japan
Laboratory of Molecular Cell Biology, Graduate School of Biostudies, Kyoto
University, Kyoto, Japan
Takeo Fukuzumi Department of Regulatory Bioorganic Chemistry, The Institute
of Scientific and Industrial Research, Osaka University, Osaka, Japan
Susana P. Gaudêncio Center for Marine Biotechnology and Biomedicine,
Scripps Institution of Oceanography, University of California, San Diego, La Jolla,
CA, USA
Masaki Hagihara Department of Regulatory Bioorganic Chemistry, The Institute
of Scientific and Industrial Research, Osaka University, Osaka, Japan
Masatoshi Hagiwara Department of Anatomy and Developmental Biology,
Graduate School of Medicine, Kyoto University, Kyoto, Japan
Futoshi Hasegawa Department of Chemistry, Graduate School of Science, Osaka
University, Osaka, Japan
Go Hirai Synthetic Organic Chemistry Laboratory, RIKEN Advanced Science
Institute, Saitama, Japan
Changfeng Hong Department of Regulatory Bioorganic Chemistry, The Institute
of Scientific and Industrial Research, Osaka University, Osaka, Japan
Sakiko Honjoh Department of Cell and Developmental Biology, Graduate School
of Biostudies, Kyoto University, Kyoto, Japan
Yimin Hua Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
Chambers C. Hughes Center for Marine Biotechnology and Biomedicine,
Scripps Institution of Oceanography, University of California, San Diego, La Jolla,
CA, USA
Gene Hung Isis Pharmaceuticals, Carlsbad, CA, USA
Hidenori Ichijo Laboratory of Cell Signaling, Graduate School of Pharmaceutical
Sciences, The University of Tokyo, Tokyo, Japan
Masayuki Igarashi Laboratory of Disease Biology, Institute of Microbial
Chemistry, Tokyo, Japan
Masamitsu Iino Department of Pharmacology, Graduate School of Medicine,
The University of Tokyo, Tokyo, Japan
Mark von Itzstein Institute for Glycomics, Griffith University, Gold Coast
Campus, Southport, QLD, Australia
Paul R. Jensen Center for Marine Biotechnology and Biomedicine, Scripps
Institution of Oceanography, University of California, San Diego, La Jolla, CA, USA
Contributors xiii

Miki Kamiyama Laboratory of Cell Signaling, Graduate School of Pharmaceutical

Sciences, The University of Tokyo, Tokyo, Japan
Motomu Kanai Graduate School of Pharmaceutical Sciences, The University of
Tokyo, Tokyo, Japan
Reiji Kannagi Research Complex for Medical Frontiers, Aichi Medical University,
Aichi, Japan
Department of Molecular Pathology, Aichi Cancer Center, Nagoya, Japan
Laura L. Kiessling Departments of Chemistry and Biochemistry, University of
Wisconsin-Madison, Madison, WI, USA
Yoshito Kishi Department of Chemistry and Chemical Biology, Harvard University,
Cambridge, MA, USA
Motomasa Kobayashi Graduate School of Pharmaceutical Sciences, Osaka
University, Osaka, Japan
Yamato Kojimoto Department of Biological Sciences, Graduate School of Science
and Technology, Kumamoto University, Kumamoto, Japan
Keiichi Konoki Graduate School of Agricultural Science, Tohoku University,
Sendai, Japan
Naoyuki Kotoku Graduate School of Pharmaceutical Sciences, Osaka University,
Osaka, Japan
Nobuhiro Koyama Graduate School of Pharmaceutical Sciences, Kitasato
University, Tokyo, Japan
Adrian R. Krainer Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
Tomohiro Kurosaki Laboratory for Lymphocyte Differentiation, WPI Immunology
Frontier Research Center, Osaka University, Osaka, Japan
RIKEN Research Center for Allergy and Immunology, Kanagawa, Japan
James J. La Clair Xenobe Research Institute, San Diego, CA, USA
Fu-Sen Liang Howard Hughes Medical Institute, Stanford University School of
Medicine, Stanford, CA, USA
Clifford A. Lowell Department of Laboratory Medicine, University of California,
San Francisco, CA, USA
John B. MacMillan Center for Marine Biotechnology and Biomedicine, Scripps
Institution of Oceanography, University of California, San Diego, La Jolla, CA, USA
Nobuaki Matsumori Department of Chemistry, Graduate School of Science,
Osaka University, Osaka, Japan
Yota Matsuo Department of Biological Sciences, Graduate School of Science
and Technology, Kumamoto University, Kumamoto, Japan
xiv Contributors

Yuki Mihara Department of Biological Sciences, Graduate School of Science

and Technology, Kumamoto University, Kumamoto, Japan
Hiroyuki Miyachi Graduate School of Medicine, Dentistry and Pharmaceutical
Sciences, Okayama University, Okayama, Japan
Asako Murata Department of Regulatory Bioorganic Chemistry, The Institute of
Scientific and Industrial Research, Osaka University, Osaka, Japan
Michio Murata Department of Chemistry, Graduate School of Science, Osaka
University, Osaka, Japan
Takeharu Nakashima Department of Chemistry, Graduate School of Science,
Osaka University, Osaka, Japan
Kazuhiko Nakatani Department of Regulatory Bioorganic Chemistry, The Institute
of Scientific and Industrial Research, Osaka University, Osaka, Japan
Eisuke Nishida Department of Cell and Developmental Biology, Graduate School
of Biostudies, Kyoto University, Kyoto, Japan
Kunihiko Nishino Laboratory of Microbiology & Infectious Diseases, Institute
of Scientific and Industrial Research, Osaka University, Osaka, Japan
Katsuyuki Ohmori Department of Clinical Pathology, Kyoto University School
of Medicine, Kyoto, Japan
Tohru Oishi Department of Chemistry, Faculty and Graduate School of Sciences,
Kyushu University, Fukuoka, Japan
Shinji Oki Department of Immunology, National Institute of Neuroscience,
National Center of Neurology and Psychiatry, Tokyo, Japan
Hiroyuki Osada Chemical Biology Department, RIKEN Advanced Science
Institute, Saitama, Japan
Ryota Ouda Laboratory of Molecular Genetics, Institute for Virus Research,
Kyoto University, Kyoto, Japan
Laboratory of Molecular Cell Biology, Graduate School of Biostudies, Kyoto
University, Kyoto, Japan
Ronald T. Raines Department of Biochemistry, University of Wisconsin-Madison,
Madison, WI, USA
Benjamin J.E. Raveney Department of Immunology, National Institute of
Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
Frank Rigo Isis Pharmaceuticals, Carlsbad, CA, USA
Kentaro Sahashi Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
Contributors xv

Keiichiro Sakuma Research Complex for Medical Frontiers, Aichi Medical

University, Aichi, Japan
Department of Molecular Pathology, Aichi Cancer Center, Nagoya, Japan
Takehiro Sato Laboratory of Cell Signaling, Graduate School of Pharmaceutical
Sciences, The University of Tokyo, Tokyo, Japan
Masakatsu Shibasaki Institute of Microbial Chemistry, Tokyo, Japan
Kaya Shigaki Department of Biological Sciences, Graduate School of Science
and Technology, Kumamoto University, Kumamoto, Japan
Siro Simizu Chemical Biology Department, RIKEN Advanced Science Institute,
Saitama, Japan
Department of Applied Chemistry, Faculty of Science and Technology, Keio
University, Yokohama, Japan
Mikiko Sodeoka Synthetic Organic Chemistry Laboratory, RIKEN Advanced
Science Institute, Saitama, Japan
Peter Stoilov Department of Biochemistry, West Virginia University, Morgantown,
WV, USA
Kohsuke Takeda Division of Cell Regulation, Graduate School of Biomedical
Sciences, Nagasaki University, Nagasaki, Japan
Rie Tamate Department of Chemistry, Graduate School of Science, Osaka
University, Osaka, Japan
Tokio Tani Department of Biological Sciences, Graduate School of Science and
Technology, Kumamoto University, Kumamoto, Japan
Kazuaki Tokunaga Department of Biological Sciences, Graduate School of
Science and Technology, Kumamoto University, Kumamoto, Japan
Hiroshi Tomoda Graduate School of Pharmaceutical Sciences, Kitasato University,
Tokyo, Japan
Kohei Torikai Department of Chemistry, Faculty and Graduate School of Sciences,
Kyushu University, Fukuoka, Japan
Ayako Tsuchiya Synthetic Organic Chemistry Laboratory, RIKEN Advanced
Science Institute, Saitama, Japan
Motonari Uesugi Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto
University, Kyoto, Japan
Institute for Chemical Research, Kyoto University, Kyoto, Japan
Shiori Umemoto Department of Regulatory Bioorganic Chemistry, The Institute
of Scientific and Industrial Research, Osaka University, Osaka, Japan
xvi Contributors

Masaharu Uno Department of Cell and Developmental Biology, Graduate School

of Biostudies, Kyoto University, Kyoto, Japan
Herbert Waldmann Chemical Biology Department, Max Planck Institute of
Molecular Physiology, Dortmund, Germany
Hiroaki Yagi Department of Biological Sciences, Graduate School of Science
and Technology, Kumamoto University, Kumamoto, Japan
Takashi Yamamura Department of Immunology, National Institute of
Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
Jinhua Zhang Department of Regulatory Bioorganic Chemistry, The Institute of
Scientific and Industrial Research, Osaka University, Osaka, Japan
Slava Ziegler Chemical Biology Department, Max Planck Institute of Molecular
Physiology, Dortmund, Germany
 Part I
Chembiomolecular Chemistry
Chemistry of Mycolactones, the Causative
Toxins of Buruli Ulcer

Yoshito Kishi

Introduction

Buruli ulcer is a severe and devastating skin disease caused by Mycobacterium

ulcerans infection, yet it is one of the most neglected diseases (Fig. 1) (for recent
reviews on Buruli ulcer, see [1–3]). Among the diseases caused by mycobacterial
infection, Buruli ulcer occurs less frequently than tuberculosis (Mycobacterium
tuberculosis) and leprosy (Mycobacterium leprae). However, it is noted that the
occurrence of Buruli ulcer is increasing and spreading in tropical countries, and that
the incidence of the disease may exceed that of leprosy and tuberculosis in highly
affected areas. Infection with M. ulcerans, probably carried by aquatic insects and
mosquitoes [4, 5], results in painless necrotic lesions that, if untreated, can extend
to 15% of a patient’s skin surface. Surgical intervention has been the only practical
curative therapy for Buruli ulcer.
Most pathogenic bacteria produce toxins that play an important role(s) in dis-
ease. However, there has been no evidence thus far to suggest toxin production by
M. tuberculosis and M. leprae. Interestingly, the presence of a toxin in M. ulcerans
had been noticed for many years, but the toxin was not isolated until 1999 when
Small and co-workers succeeded in isolation and characterization of mycolactone
A/B from this bacteria [6]. Intradermal inoculation of mycolactone A/B into guinea
pigs produces lesions similar to that of Buruli ulcer in humans, demonstrating their
direct correlation with Buruli ulcer ([7]: for recent reviews on mycolactones, see
[8, 9]).

Y. Kishi (*)
Department of Chemistry and Chemical Biology, Harvard University,
12 Oxford Street, Cambridge, MA 02138, USA
e-mail: [email protected]

M. Shibasaki et al. (eds.), Chembiomolecular Science: At the Frontier 3

of Chemistry and Biology, DOI 10.1007/978-4-431-54038-0_1, © Springer Japan 2013
4 Y. Kishi

Fig. 1 Buruli ulcer lesion (taken from [1])

Structure

Gross Structure

The gross structure of mycolactone A/B was elucidated by Small and co-workers
via a variety of spectroscopic methods; coupled with mass spectroscopy (MS),
ultraviolet (UV), and infrared (IR) studies, extensive two-dimensional nuclear mag-
netic resonance (2D NMR) experiments led them to suggest the gross structure of
mycolactone A/B [10].

Stereochemistry

For the proposed gross structure of mycolactone A/B, 1,024 stereoisomers are pos-
sible. Considering the limited availability, as well as the noncrystallinity, of mycolac-
tone A/B, we recognized the difficulties that might be encountered in the assignment
of its stereochemistry. Coincidentally, we were then engaged in the development of
the universal NMR database approach to assign the relative and absolute configuration
of unknown compounds without degradation or derivatization, and we noticed that
the universal NMR database approach was uniquely suited to assign the stereo-
chemistry of the mycolactone A/B ([11, 12] and references cited therein). Indeed,
with use of this approach, we could establish the complete structure of the mycolac-
tone A/B (Fig. 2) [13, 14]. Mycolactone A/B exists as a 3:2 equilibrating mixture,
with the major and minor components corresponding to the Z-D4¢,5¢- and E-D4¢,5¢-
isomers, respectively, in the unsaturated fatty acid side chain.