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VSS2021 - Session 3 (07-06-21)

This document summarizes recent research on cytotoxic compounds from Indonesian Aglaia plants. It describes how several research studies have isolated and characterized various bioactive compounds from different Aglaia species native to Indonesia, including dammarane triterpenoids from A. smithii and A. glabrata, stigmastane steroids from A. eximia, bisamide and lignan compounds from A. eximia, apotirucallane triterpenoids and rocaglate from A. argentea, and sesquiterpenoids from A. hamsiana. The document outlines the isolation procedures used to obtain these cytotoxic and potentially anti-cancer compounds from various Indonesian Aglaia

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Muhammad Zakiy Fadlullah
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35 views

VSS2021 - Session 3 (07-06-21)

This document summarizes recent research on cytotoxic compounds from Indonesian Aglaia plants. It describes how several research studies have isolated and characterized various bioactive compounds from different Aglaia species native to Indonesia, including dammarane triterpenoids from A. smithii and A. glabrata, stigmastane steroids from A. eximia, bisamide and lignan compounds from A. eximia, apotirucallane triterpenoids and rocaglate from A. argentea, and sesquiterpenoids from A. hamsiana. The document outlines the isolation procedures used to obtain these cytotoxic and potentially anti-cancer compounds from various Indonesian Aglaia

Uploaded by

Muhammad Zakiy Fadlullah
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
Available Formats
Download as PDF, TXT or read online on Scribd
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VIRTUAL SUMMER SCHOOL

2021

UNIVERSITAS PADJADJARAN UNIVERSITAS PENDIDIKAN INDONESIA

Recent Study on Cytotoxic Compounds


from Indonesia Aglaia Plants

Unang Supratman1,2

1Departemen of Chemistry, Faculty of Mathematics and Natural


Sciences, Universitas Padjadjaran, Jatinangor 45363, Indonesia

2Central
Laboratory, Universitas Padjadjaran, Jatinangor,
Indonesia
E-mail: [email protected]
Cytototoxic

 Cytotoxicity is the quality of being toxic to cells


 Treating cells with the cytotoxic compound can
result in a variety of cell fates.
 The cells may undergo necrosis, in which they
lose membrane integrity and die rapidly as a
result of cell lysis.
 The cells can stop actively growing and dividing
(a decrease in cell viability), or the cells can
activate a genetic program of controlled cell
death (apoptosis).
Anti-cancer
 Anticancer definition is - used against or
tending to arrest or prevent cancer.
 anti-cancer drugs (chemotherapeutic agents)
 The term chemotherapy has come to connote
non-specific usage of intracellular poisons to
inhibit mitosis (cell division) or induce DNA
damage, which is why inhibition of DNA repair,
augmented with specific molecular or genetic
targets, which inhibit growth-promoting signals
from classic endocrine hormones
Cytotoxic and Cancer
Why Cancer?
 One of the deadliest diseases in the world
(1 in 4 deaths are due to cancer)

 The number of cancer sufferers in the world is


increasing by around 7 million people / year,
two thirds of them are in developing countries

 26 million people will suffer from cancer and


17 million die of cancer by 2030
Cancer in Indonesia

The Global Cancer Observatory - All Rights Reserved - May, 2019.


Types of Cancer Treatment
❑ Surgery
❑ Radiation Therapy
❑ Chemotherapy
❑ Immunotherapy
to Treat Cancer
❑ Targeted Therapy
❑ Hormone Therapy
❑ Stem Cell Transplant
❑ Precision Medicine
Chemotherapy Substances

Capecitabine Erlotinib Rheumatrex


Side Effects of Chemotherapy
• Anemia • Hair Loss (Alopecia)
• Appetite Loss • Infection and Neutropenia
• Bleeding and Bruising • Lymphedema
(Thrombocytopenia) • Memory or Concentration
• Constipation Problems
• Delirium • Mouth and Throat Problems
• Diarrhea • Nausea and Vomiting
• Edema (Selling) • Nerve Problems (Peripheral
• Fatigue Neuropathy)
• Fertility Issues • Organ-Related Inflammation
• Flu-Like Symptoms and Immunotherapy
• Sexual Health Issues in Men • Pain
• Sexual Health Issues in Women
• Skin and Nail Changes
• Sleep Problems
• Urinary and Bladder Problems
Current Anticancer Drugs from Plants

Nimbolida

Taxus brevifolia Catharanthus roseus Azadirachta indica


Indonesian Tropical Plants

(Christenhusz and Byng, 2016; Koenen et al., 2015)


Meliaceae (Mahogany Family)

50 genus and
MELIACEAE
650 spesies
(Mahagony)

The largest genus, with


around 120 species Aglaia

Pannell, 1992
Aglaia Plants

Largest genus of
Meliaceae family

▪  65 species grow in
Indonesia
▪ Traditional used
▪ Exhibited biological
activities
▪ Interesting class of
natural products
▪ Largely unexplored

Distributed in
tropical forest

Mabberley, 1995 and Pannel, 1992


Distribution of Aglaia Species in the World

Sothern China
Taiwan

Burma Thailand

Philiphines

Malaysia Papua New


Guinea
Indonesia

Mabberley, 1995 and Pannel, 1992


Distribution of Aglaia Species in Indonesia

12 plant species 35 Plant species

15 plant species

6 plant species

11 plant species Bogor Botanical Garden, Indonesia;


Heyne, 1982
Pharmacological activity of some of
the Aglaia plants
Species Pharmacology activities
A. abbreviata Cytotoxic
A. forbessi Antifungi
A. ignea Antiretroviral
A. odorata Anti-inflammatory, antitumor
A. roxburghiana Anti-inflammatory
A. perviridis Inhibition of NO production
A. oligophylla Insecticidal
A. elliptifolia Cytotoxic
A. foveolata Cytotoxic
A. crassinervia Cytotoxic

Liu et al., 2014; Cai et al., 2010


Traditional Uses

❑ Furniture
❑ Reinforcing the liver
❑ Fever
❑ Cough medicine
❑ Inflammation and infection
❑ Bactericides
❑ Insecticides
❑ Fragrances
Currently investigated species of
Indonesia Aglaia plants in Indonesia

 A. cordata  A. minahassae  A. smithii


 A. elliptifolia  A. simplicifolia  A. kortalsii
 A. edulis  A. spectabilis  A. rubiginosa
 A. duperreana  A. argentea  A. versteghii
 A. odorata  A. glabrata  A. pachyphyla
 A. elaegnoidea  A. abbreviata  A. ignea
 A. eximia  A. perviridis  A. cucculata
 A. crassinervia  A. odoratisima  A. euporoides
 A. grandis  A. dookkoo  A. elliptica
 A. Silvestris  A. sapindina  A. foveolata
 A. angustifolia  A. tomentosa  A. hamsiana

Bogor Botanical Garden, Indonesia


MTT Assay (P-388 Murine Leukemia
and MCF-7 cell lines, in vitro)

Alley., 1988
Cell Cytotoxic Test (Resazurin
Reduction Method)
A. smithii and A. eximia

Desi Harneti
Ph.D Student
(2005-2010)

A. smithii A. eximia

Batukanag (Sulawesi) Oro-oro (Sumatera)


Alawe (Papua)
Strategy for bioactive compound
Isolation Procedure for Active Compounds
Dammarane-type Triterpenoids
(A. smithii)

Harneti et al., Phytochem. Lett., 2012, 5, 496–499.


13C-NMR Spectrum of Aglinone

CH=
DEPT-135

O-C-O
O-C=
C=O
1H-NMR Spectrum of Aglinone
ORTEP Drawing of Aglinin A

Harneti et al., Acta Cryst. (2010). E66, o416 E


Stigmastane-type Steroids
(A. eximia)

Harneti et al., Phytochemistry Letters, 2014, 828–31


13C-NMR Spectrum of 3,4-epoxy-22R,25-
epoxy-stigmast-5,20-dien

CH3
C-O C-O
CH=

CH2=
CH2
1H-NMR Spectrum of 3,4-epoxy-22R,25-
epoxy-stigmast-5,20-dien

CH3
A. glabrata

Asep Supriadin
Ph.D Student
(2010-2015)

A. glabrata

local name Jentikkan


(Sumatera)
Dammarane-type Triterpenoids
(A. glabrata)

Supriadin et al., RJPBCS, 2018, 9(3), 1017-1021


ORTEP Drawing for (20S)-Dammar-24-
ene-3a,20b-diol

Supriadin et al., Acta Cryst. (2012). E68, o2712–o2713


A. eximia

Julinton Sianturi
Master Student
(2014-2016)

A. eximia
Bisamide Compounds from A. eximia

Sianturi et al., Phytochem. Lett., 2015, 13, 297–301


13C-NMR Spectrum of Exiamide A
1H-NMR Spectrum of Exiamide A
Lignan Compounds from A. eximia

Sianturi et al., Natural Product Research, 2016, 1, 1-6


13C-NMR Spectrum of Lignan
1H-NMR Spectrum of Lignan
A. argentea and A. elliptica

Kindi Farabi
Master Student
(2015-2016)

A. argentea A. elliptica

local name Local name is Laban Abang


langsat hutan (Java) (Sulawesi)
Apotirucallane-type Triterpenoids
(A. argentea)

Farabi et al., Phytochem. Lett., 2017, 21, 211-215


1H-NMR Spectrum of Argentinin A
13C-NMR Spectrum of Argentinin A
Rocaglate from the bark of A. argentea

Farabi et al., Molekul, 2017, 12(2), 146-152


Sitosterol from the bark of A. elliptica

Farabi et al., Rec. Nat. Prod. 2018, 12:2, 121-127


Farabi et al., CMU J. Nat. Sci. 2017, 16(4), 293-306
1H-NMR Spectrum of 2a-hydroxy-3a-
methoxy-5a-pregnane
13C-NMR Spectrum of 2a-hydroxy-3a-
methoxy-5a-pregnane
A. hamsiana

Hersa Milawati
Master Student
(2017-2019)

A. harmsiana
Sesquiterpenoids (A. harmsiana)

Milawati et al., Molekul, 2019, 14(2), 126-132


Milawati et al., Indones. J. Chem., 2020, 20 (6), 1448 - 1454
A. angustifolia

Ricson P. Hutagaol
Ph.D Student
(2016-2020)

A. angustifolia
Cholestane-type steroid from A. angustofolia

Hutagaol et al., Molbank 2020, M1112; doi:10.3390/M1112


Seco-apoticulane and Dammarane-type
from A. angustifolia

Hutagaol et al., Journal of Asian Natural Products Research, 1, 1-12


Summary
 Ten cytotoxic groups have been isolated from
Indonesia Aglaia plants
 Dammarane-type triterpenoid is most
abundance of secondary metabolites
 Methyl rocaglate showed strongest cytotoxic
activity against P-388 murine leukimia cells in
vitro (IC50  0.1 mg/mL)
Review;
Phytochemistry and biological activities of
Aglaia Species
Potent Compounds from Aglaia for
anti-cancer

Methyl rocaglate
(IC50 < 0.1 mM)
A. rubiginosa
A. argentea IC50  0.1 mM

Kinghorn et al., J. Nat. Prod. 2004, 67, 343-347


An et al., , Nature, 2016, 6, 20045
Total Synthesis of Rocaglate

Adam et al., J. Am. Chem. Soc. 2009, El Sous et al., Angew. Chem. Int. Ed. 2007,
131, 1607–1616 46, 7835 –7838
Retrosynthetic Analysis

Adam et al., J. Am. Chem. Soc. 2009,


131, 1607–1616
On Going Research
 Aglaia species from Borneo (Kalimantan)
▪ A. pachyphylla
▪ A. cucullate
▪ A. crassinervia
▪ A. laxiflora
❑ Endophytic fungi from Aglaia elliptica
❑ Synthesis total of Rocaglate
Acknowledments

❑ Ministry of National Education, Indonesia


(Postgraduate Grant by US, 2004-2007)
❑ Ministry of National Education, Indonesia
(International Grant by US, 2012-2016)
❑ Third World Academic Sciences (TWAS) Grant,
(2016-2018 by US)
❑ Universitas Padjadjaran, Academic Leadership
Grant, since 2014, by US
Thank You
Research Group on Natural Product Chemistry
Universitas Padjadjaran

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