chemical prospecting from indonesian rainforest...
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CHEMICAL PROSPECTING FROM INDONESIAN RAINFOREST PLANTS
Sjamsul Arifin Achmad, Euis Holisotan Hakim, Lia Dewi Juliawaty,
Lukman Makmur, Didin Mujahidin and Yana Maolana Syah
Research Group on Natural Product Chemistry
Department of Chemistry
Institut Teknologi Bandung
Indonesia
DRUGS DISCOVERY PROGRAM
ACQUIRE BIODIVERSITY
FOR FOR
BROADENING OF AVAILABLE
MOLECULAR STRUCTURES
(CHEMODIVERSITY)
FOR BIO- & AGRO-INDUSTRIES
SOME CONTEMPORARY ISSUES ON GLOBAL DEVELOPMENTS
ENVIRONMENT
BIODIVERSITY; BIOETHICSBIODIVERSITY; BIOETHICS
FOODS & HEALTH
ENERGY; MATERIALS
INFORMATION TECHNOLOGIES
NATURAL PRODUCTS IN DEVELOPMENT OF MEDICINES
• Over 120 drugs of known structures still extracted and produced commercially from only 90 species of higher plants, and used globally as a single agent drugs.
• During 1959-1980, in United States, 25% of all prescriptions dispensed from pharmacies contained active principles extracted dispensed from pharmacies contained active principles extracted from higher plants.In 1980, consumers in the United States paid more than US$ 8 billion for prescription containing active principles from higher plants.
• During 1989-1995, over 60% of approved anticancer and antiinfective agents, are of natural origin.
• Over 60% of world’s population use plants as a primary health care
• About $ 5.00 billion are used on phytotherapeutical in U.S. in 2005
• No globally available treatments for new deadly and untreatable diseases (AIDS, tuberculosis, malaria, avian flu)
GLOBAL HEALTH PROBLEMS
• Increasing drug resistance
• Exploding population
Natural product sciences must contribute in :
• Drug discovery for critical diseases
• Enhance natural product structure
THE POTENTIAL OF NATURAL PRODUCTS
IN HEALTH CARE
• Enhance natural product structure
diversification
* Phytotherapeutical standardization
Sustainable drug discovery approaches
are urgently needed for future health care
THERE IS NO DOUBT THAT PLANTS HAVE PROVIDED, AND CAN CONTINUE TO PROVIDE HUMANS WITH USEFUL DRUGS
WHAT NEXT ???
NOBODY COULD NEGLECT TO INVESTIGATE FURTHER THE ABUNDANT FLORA OF THE WORLD FOR THE PRESENCE OF NEW DRUGS THAT WILL BENEFIT THE WORLD.
BIORESOURCES
TERRESTRIAL OR MARINE ANIMALS, PLANTS
AND MICROORGANISMS
ARE ARE
CHEMICAL SYSTEMS,
ULTIMATE CHEMICAL SOURCE,
AND CHEMICAL SAFETY
IN THE 21TH CENTURY
GENETIC RESOURCES OF SOUTHEAST ASIA A SPECIAL HERITAGE
1. EVERGREEN TROPICAL RAINFOREST
2. OLDEST & MOST DIVERSE TERESTRIAL ECOSYSTEM
3. ABUNDANCE & UNPARALLELED GENETIC VARIATIONS
& HIGHLY SPECIALIZED VEGETATION
4. RICH SOURCE OF NATURAL PRODUCT CHEMICALS
SYSTEMATIC STUDY ON CHEMICAL
DIVERSITY
OF
PLANT SPECIES FROM INDONESIAN
TROPICAL FORESTS
PHYLOGENETIC
RELATIONSHIP BETWEEN
PLANTS FAMILIES
EVOLUTIONARY RELATIONSHIP BETWEEN SUB-CLASSES OF DICOTYLEDONE
Asteridae
Rosidae
Carryophyllidae
Magnoliidae
Hamamelidae Dilleniidae
Carryophyllidae
Lit.: O.P Gottlieb, “Chemosystematic of the Lauraceae”, Phytochemistry, 1972, 11. 1537-1570
• Large family consists of 3000 species from the most primitive sub-class Magnoliidae of the flowering plants
• Tropical plants, 600 species are found and widely distributed in Indonesia
• Has been used as traditional medicines, edible
WHY LAURACEAE ???
• Has been used as traditional medicines, edible fruits, spices, perfume oils and for its timber
• Exhibited useful biological activities
• Contains interesting class of natural product compounds
• Largely unexplored
DISTRIBUTION OF LAURACEAE IN INDONESIA
EVOLUTIONARY AFFINITIES AMONG SUBTRIBES
OF LAURACEAE (KOSTERMANS, 1957)
PERSEINEAE
BEILSCHMIEDINEAE
CINNAMOMINEAECINNAMOMINEAE
CRYPTOCARYINEAE
EUSIDEROXYLINEAE
LITSEINEAE
LAURINEAEANABINEAE
CHEMICAL RELATIONSHIP BETWEEN VARIOUS
SUBTRIBES OF LAURACEAE (GOTTLIEB, 1972)
PERSEINEAE
BEILSCHMIEDINEAE
Alkaloid precursor
CINNAMOMINEAE
Alkaloids A
Arylpropanoids
LITSEINEAE
LAURINEAE
CRYPTOCARYINEAE
Alkaloids A,B,C
Arylpropanoids
ANABINEAE
Alkaloids
“Advanced”
Flavonoids
Sesquiterpenes
“Primitive”
Arylpropanoid
2-Pyrones
Flavonoids
Benzophenone
PHARMACOLOGICAL ACTIVITY OF SOME OF THE LAURACEAE
Species Pharmacological activities
Actinodaphne nitida
Teschn.Beilschmiedia elliptica C. White
B. podagrica Kosterm.
Cassytha filiformis L.
Cinnamomum baileyanum
(F.Muell ex Bailey) Francis
Cryptocarya bowiei Druce
C. fluminensis Kosterm.
C. laevigata Bl.
C. laevigata var. bowiei
Cardiovascular
Antispasmodic
Cardiovascular; Analgesic; Antipyretic
Central nervous system; cardiovascular;
Diuretic
Antitumor
Antitumor
Antitumor;
Hypotensive; Anticonvulsant; Analgesic
Antitumor
Antitumor
AntitumorC. laevigata var. bowiei
C. microneura Meissner
C. multinervis Teschn.
C. multipaniculata Teschn.
C. pleurosperma C. White
Litsea glutinosa
(Lour)C.E.Rob
Litsea sp. aff. glutinosa
(Lour.)
Litsea timoriana Span.
Phoebe forbesii Gamble
Antitumor
Antitumor
Antitumor; Vesicant; Hypotensif;
Antiviral; Inhibitor protein synthesis
Hypotensive; Analgesic; Antipiretic
Antitumor
Antiinflamation; Diuretic
Hypotensif; Antimicrobial; Diuretic
Antitumor
Antiinflammatory, Diuretic
Hypotensive, Antimicrobial, Diuretic
Lit.: D.J. Collins, C.C.J. Culvenor, J.A. Lamberton, J.W. Loder and J.R. Price, “Plants of Medicines –
A Chemical and Pharmacological Survey of Plants in the Australian Region”, CSIRO, Australia (1990).
• LONG ISOLATION FOR UNIQUENESS OF FLORA
• HIGH ENDEMICITY
•WIDE VARIETY OF BIOTOPES
CHARACTERISTIC OF TARGETED FLORA
•WIDE VARIETY OF BIOTOPES
• DIVERSIFIED - FROM ANCESTRAL TO MODERN TAXA
• DISTRIBUTION OF SPECIES
• Actinodaphne glomerara • Cryptocarya strictifolia• C. densiflora• C. massoia• C. ferrea• C. idenburgensis
• L. diversifolia• L. elliptica• L. excelsa• L. firma• L. glurinosa • L. grandis
CURRENTLY INVESTIGATED SPECIES
OF INDONESIAN LAURACEOUS PLANTS
• C. idenburgensis • C. kamahar• C. laevigara• C. nutans• Litsea amara• L. cassiaefolia• L. cubeba
• L. grandis• L. monoperala • L. tomenrosa• Neolitsea cassiaefolia• Persea rimosa
INDONESIOL A NEW SESQUITERPENE FROM
LITSEA AMARA BL. (LAURACEAE)
OH
Indonesiol
Lit.: Achmad, S.A., Ghisalberti, E.L., Hakim, E.H., Makmur, L., Manurung, M. (1992a). A
sesquiterpene alcohol from Litsea amara, Phytochemistry, 31(6), 2153-2154
A NEW MAJOR SESQUITERPENE FROM
LITSEA EXCELSA NEES (LAURACEAE)
OH
OH
8-Hydroxycusunol
Lit.: Hakim. E.H.. Achmad, S.A., Effendy. Ghisalberti. E.L.. David C.R. Hockless, D.C.R
and White, A.H.. "Structural studies of three sesquiterpenes from Litsea spp.
(Lauraceae)", Aust. J. Chem., 46, 1355 -1362 (1993)
NEW SESQUITERPENES FROM LITSEA
CASSIAEFOLIA BL. (LAURACEAE)
O
HO
OH
H
H3C
OHO
O
Litseacassifolide
H
H3C
H
Isocurcumol
Lit.: Hakim. E.H.. Achmad, S.A.. Effendy, Ghisaiberti. E.L.. David C.R. Hockless,
D.C.R and White. A.H., Structural studies of three sesquiterpenes from Litsea spp.
(Lauraceae), Aust. J. Chem., 46,1355 -1362 (1993)
DEGREE OF BIOGENETIC COMPLEXITY OF NEW SESQUITERPENES DERIVED FROM LAURACEAE
OH
OH
OH
Indonesiol
(Secoiswarane)
O
O
O
O
O
H
H3C
O
H
OH
H
O
HCO2OH
OHO
Litseacassifolide
(Germacrane)
8-Hidroxycusunol
(Eremofilane)
Isocurcumol Neoserisealactonic acid(Guaian) (Elemane)
• MORACEAE CONSISTS OF 50 GENERA AND 1500 SPECIES IN
THE FORM OF TREE OR SHRUBS BUT RARELY HERBS
• MOSTLY FOUND IN TROPICAL AND SUB TROPICAL ZONES
• MORE THAN 80 SPECIES MAY BE FOUND IN INDONESIA.
HOWEVER SCIENTIFICALLY UNEXPLORED
WHY MORACEAE ???
HOWEVER SCIENTIFICALLY UNEXPLORED
• ECONOMICALLY IMPORTANT AS EDIBLE FRUITS, MEDICINAL
PLANTS, FOOD FOR SILKWORMS, FLAVOURINGS, TIMBERS
• PRODUCE INTERESTING CHEMICALS: SUCH AS FLAVONOID,
XANTHONE, STILBEN, ARYLBENZOFURAN, DIEL-ALDER TYPE
ADDUCT, ALKALOID AND CARDENOLIDE
• EXHIBITED USEFUL BIOLOGICAL AND PHARMACOLOGICAL
ACTIVITIES: ANTI-HYPERTENSIVE, ANTITUMOR, ANTIDIABETIC,
ANTI MICROBIAL, JUVENOMIMETIC
• Artocarpus altilis (Park)Fobs.
• Artocarpus bracteata
• Artocarpus champeden
• Artocarpus maingayii
• Artocarpus nitidus Trec.
• Artocarpus reticulatus
CURRENTLY INVESTIGATED SPECIES OF
INDONESIAN MORACEOUS PLANTS
• Artocarpus dadah Miq.
• Artocarpus dasyphyllus
• Artocarpus gomezianus Wall.
• Artocarpus kemando
• Artocarpus lanceifolius
• Artocarpus rotundas
• Artocarpus scortechinii
• Artocarpus teysmanii
• Artocarpus sp.
• Morus macroura Miq.
Degree of biosynthetic
complexity and
cytotoxicity against P-388
cell-line of the flavonoids
derived from Artocarpus
O
OHHO
HO
O
OO
HO
OH
OHHO
O
OOH
HO
O
OH
CO2CH3
O
OOH
HO
O
O
O
OO
CH2OH
OOH
HO
OHHO
e.g. ARTONOL B
IC50 >100 ug.Ml
ARTOINDONESIANIN Z-3
IC50 3.7 ug.mL
ARTOINDONESIANIN Z-1
IC50 5.9 ug/mL
e.g. ARTOINDONESIANIN C
IC50 6.2 ug/mL
O
O
O
HO CO2CH3
O
OH
HO
O
OOH
OHHO
CH3O
O
OHHO
OOH
HOOH
OOH OOH
OH
O
OOH
HO
O
OH
OH
O
OHHO
OOH
HO
O
O
OOH
HO
OH
ARTOINDONESIANIN P
IC50 4.6 ug/mL
ARTOINDONESIANIN Z-2
IC50 1.6 ug/mL
e.g. ARTOBILOXANTHONE
IC50 1.75 ug/mL
ARTOINDONESIANIN B
IC50 3.9 ug/mLe.g. ARTOINDONESIANIN
IC50 0.2 ug/mL
e.g. ARTOCARPANONE
IC50 19.3 ug/ml
e.g. ALBANIN A
IC50 2.3 ug/mL
A. altissimusA. dadah
A. lackoocha
A. elasticus
A. altilis
A. lanceifolius
PHYLOGENETIC RELATIONSHIP BETWEEN SOME SPESIES OF ARTOCARPUS
A. chaplasha
Ficus
Morus
A. nitidus
A. heterophyllus
A. integer
A. rigidus
• A LARGE FAMILY OF TROPICAL PLANTS, COMPRISES 16 GENERA AND 600
SPECIES. THE LARGEST GENERA, SHOREA (150 SPECIES) KNOWN LOCALLY
AS MERANTI.
• ESPECIALLY ABUNDANT IN THE RAINFOREST OF INDONESIA, HOWEVER A
GREAT MAJORITY HAVE NOT BEEN INVESTIGATED
• HIGHLY VALUED FOR THEIR TIMBER WHICH ARE USED IN BUILDING
WHY DIPTEROCARPACEAE ???
• HIGHLY VALUED FOR THEIR TIMBER WHICH ARE USED IN BUILDING
CONSTRUCTIONS, MEDICINAL APPLICATION AND SPICES
• CONTAINS VARIETY OF ATTRACTIVE PHENOLIC COMPOUNDS, INCLUDING
OLIGOSTILBENOIDS, FLAVONOIDS, AND PHENYLPROPANOIDS
* MANY OF THE STILBENOIDS SHOWED USEFUL BIOLOGICAL ACTIVITIES : ANTI-
HIV, ANTIBACTERIAL, ANTIFUNGAL, ANTIINFLAMMATION, CYTOTOXIC,
HEPATOPROTECTIVE, INHIBITOR 5α-REDUCTASE AND ACETYLCHOLINE
ESTERASE.
• Anisoptera marginata
Korth.
• Dipterocarpus grandifolius
Blco.
• Dipterocarpus intricatus
• Shorea leprosula Miq.
• Shorea pinanga
Scheff.
• Shorea selanica
Blume
CURRENTLY INVESTIGATED SPECIES OF
INDONESIAN DIPTEROCARPACEAE
• Dipterocarpus intricatus
• Dryobalanops oblongifolia
• Hopea dryobalanoides
• Shorea balangeran Burck.
• Shorea multiflora Burck.
• Shorea guiso Blume
Blume
• Shorea seminis V. SI.
• Shorea stenoptera
• Vatica pauciflora
Blume
• Vatica umbonata
Korth.
DIPTOINDONESIN-A AND RELATED STILBENOIDS
FROM SHOREA SEMINIS
Lit.: Aminah, N.S., Achmad, S.A., Aimi, N., Ghisalberti, E.L., Hakim, E.H., Kitajima, M., Syah, Y.M. and
Takayama, H., Fitoterapia, 73, 501-507 (2002).
O
HO
H
H
HH
OH
HO
HO
O
HO
H
H
HH
OH
HO
HO
cis- AND trans-DIPTOINDONESINS - B FROM
DRYOBALANOPS OBLONGIFOLIA
(DIPTEROCARPACEAE)
O
H
OH
HO
HO
O
HHO
OH
OH
cis-Diptoindonesin - B trans-Diptoindonesin - B
Lit.: Syah, Y.M., Aminah, N.S., Hakim, E.H., Aimi, N., Kitajima, M., Takayama, H., and Achmad, S.A.,
Phytochemistry, 63, 913-917 (2003).
DIPTOINDONESINS C - E FROM VATICA PAUCIFLORA (DIPTEROCARPACEA)
HO
HO
OH
H
HO
OH
OH
OH
C1
C2
D1
D2
HO
HO
OH
H
HO
OH
OH
OH
C1
C2
D1
D2
R=H : Diptoindonesin - C
R=Gluc : Diptoindonesin - D
Diptoindonesin - E
G2
G1
F2
F1
E2
E1
OHO
HO
HO
OH
H
H
HH H
H
H
OH
O
OH
HH
OH
OH
OH
OH
HO
H
H
H
RO
A1
A2
B1
B2
OHO
HO
HO
OH
H
H
HH H
H
H
OH
OH
H
H
H
HO
OH
OH
HO
F2
F1
E2
E1
A1
A2
B1
B2
O OH
HO
OH
HO
OH
H
H
A1
A2
B1
B2
OH
OH
OHHO
HO
HO
H
H
H
H
SOME FURTHER STILBENOIDS FROM VATICA PAUCIFLORA (DIPTEROCARPACEA)
O
OH
OH
OH
OHOH
HO
HO
HOH
HH
H
H
H
OH
OH
OH
OH
HO
HO
HO HO
OH
H
H H
H
HH
OH
H
HH
H
H
HO
HO
OH
OH
OHOH
HO
HHO
OH
e-Viniferin Ampelopsin F
Stenophylol B Copallyferol A Vaticanol G
O O
OH
OHHO
HO OH
H
H
H
H
DIPTOINDONESIN - F AND NEW STILBENOID
(+) – STENOFILLOL FROM DIPTEROCARPUS
INTRICATUS DYER. (DIPTEROCARPACEAE)
OHO
HOH
OH
OHHO
OH
O
OH
OH
HO
HH
(+) - DIPTOINDONESIN - F
O
HH
H
OH
H
H
OH
HO
HO
OH
OH
OH
(+) – STENOFILLOL – C
DIPTOINDONESIN - G AND RELATED STILBENOIDS
FROM HOPEA DRYOBALANOIDES MIQ
Literature:
Sahidin, Hakim, E.H., Jualiawaty, L.D., Syah, Y.M., Din, L.B., Ghisalberti, E.L., Latip, J., Said, I.M., Achmad, S.A., Z. Naturforsch, 60c, 273-277 (2005).
SOME FURTHER STILBENOIDS FROM
HOPEA DRYOBALANOIDES MIQ
O O
HO OH
OHHOO O
HO OH
OHHO
DIPTOINDONESIN – H FROM SHOREA
PINANGA SCHEFF (DIPTEROCARPACEAE)
OH OH
OH
OH OH
OHHO
OH
Diptoindonesin - H
Ampelopsin - E
Literature : Syah, Y.M., Hakim, E.H., Ghisalberti, E.L., Jayuska, A., Mujahidin, D., Achmad, S.A., Nat. Prod. Res. (Submitted).
OH
H
OH
HO
HO
O
O
O H
HOH
OHO
H
H
OH
O
HO
OH
HO OH
H
H
OH
H
H
O
O
O
OH
OH
OH
HO
HO
HH
H
H
H
H
SOME FURTHER STILBENOIDS FROM
SHOREA PINANGA (DIPTEROCARPACEAE)
HOHOH
HO OHOH
HOO
HO
HO
OH
OH
O
OH
HOOH
OHH
H
HH
HHH
H
OH
Laevifonol Ampelopsin A a - Viniferin
Hopeaphenol
Literature :
Syah, Y.M., Hakim, E.H., Ghisalberti, E.L.,
Jayuska, A., Mujahidin, D., Achmad, S.A., Nat.
Prod. Res. (Submitted).
CYTOTOXICITY OF STILBENOIDS AGAINST HL 60 CELL LINES
O
HO
HO
OH
H
H
OH
OH
OH
H
OH
HO
HO
O
O
O
HO
H
HOH
OHO
H
H
OH
O
HO
OH
HO OH
HO
H
H
OH
H
H
e-Viniferin Laevifonol Balanocarpol
O
OO
HO
HO
OH
OH
H
H
H
H
HH
OH
OH
HOO
HO
HO
OH
OH
O
OH
HOOH
OHH
H
HH
HHH
H
OH
e-Viniferin
IC50 0.8 ug/mL
Laevifonol
IC50 0.9 ug/mLBalanocarpolIC50 0.6 ug/mL
a-Viniferin
IC50 2.1 ug/mLHopeaphenol
IC50 0.4 ug/mL
ANTIOXYDANT ACTIVITY OF STILBENOIDS
HO OH
OH
OH OH
OH
OH
OO
OH
OH
OH
CH2OH
O
HO
HO
OH
H
H
OH
OH
HO OH
OH
Resveratrol
IC50 85.6 ug/mLe-Viniferin
IC50=121.4 ug/mL
Oxyresveratrol
IC50 25.8 ug/mL
Oxyresveratrol gluc.
IC50 58.9 ug/mL
O
HO
HO
OH
H
H
OH
O
OHHOH H OH
O
HO
HO
OH
H
H
OH
O
H H OH
OH
HO
O
OO
HO
HO
OH
OH
H
H
H
H
HH
OH
OH
IC50 85.6 ug/mL
a-Viniferin
IC50 284.5 ug/mL
IC50=121.4 ug/mLIC50 25.8 ug/mL IC50 58.9 ug/mL
cis-Diptoindonesin B
IC50 76.6 ug/mLtrans-Diptoindonesin B
IC50 91.2 ug/mL
K
THE MAIN GATE OF INSTITUT TEKNOLOGI BANDUNG (ITB)
JALAN GANECA 10, BANDUNG, INDONESIA
RESEARCH GROUP OF NATURAL PRODUCTS CHEMISTRYDepartment of Chemistry, Institut Teknologi Bandung
RESEARCH GROUP OF NATURAL PRODUCTS CHEMISTRYDepartment of Chemistry, Institut Teknologi Bandung
THANK YOU
OH
HO OH
O
HO OH
O OH
OH
H
HO OH
OH
O
O
HO
OHO
HO
OHH
RADICAL TRANSFORMATION OF OLIGOSTILBENOIDS
OH
HO
H
OH
OH
HO
OH
H
O
HO
OH
HO
OH
OH
H
H
H
OH
H
O
HO
OH
HO
OH
OH
H
HH
O
OH
OH
HO
OH
OH
H
HH
H
ARRANGEMENT OF
STILBENOID DIMERS AND
TRIMERS BY BIOGENETIC
COMPLEXITY OF CARBON
SKELETON FROM
DIPTEROCARPACEAE
ARRANGEMENT OF
STILBENOIDS BY BIOGENETIC
COMPLEXITY OF CARBON
SKELETON FROM
DIPTEROCARPACEAE