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