MEDICINAL PLANTS, TRADITIONAL MEDICINEAND DRUG DISCOVERY

Gordon Cragg, Ph.D.NIH Special VolunteerNatural Products BranchDevelopmental Therapeutics ProgramDivision of Cancer Treatment and DiagnosisNCI-FrederickFairview Center, Suite 206P. O. Box BFrederick, MD 21702-1201, U. S. A.

Phone: 301-846-5387; fax: 301-846-6178e-mail: craggg@mail.nih.gov

website: http://dtp.nci.nih.gov; http://dtp.nci.nih.gov/branches/npb/index.html

EARLY DOCUMENTATION

• Mesopotamian ~2,600 BCE

• Egyptian ~ 1,800 BCE

• Chinese – since ~1,100 BCE and continuing

• Indian ~ 1,000 BCE

• Greek ~ 500 BCE

• Greco-Roman expertise preserved and coordinated with other traditionsby the Arabs during the Dark Ages ~ 400-1,100 A. D

AVICENNA. PERSIAN PHARMACIST, PHYSICIAN, POET, PHILOSOPHERAUTHOR: CANON MEDICINAE – “final codification of Greco-Roman medicine”

Traditional Medicine and Drug Discovery*

• 80% of the world population resides in developing countries

• 80% of people in developing countries utilize plants to meet their primary health care needs

• Global pop. ca. 6.3 billion – ca. 4 billion people utilize plants to

meet their primary health care needs

*Farnsworth NR, et al. Medicinal Plants in Therapy. Bull. W.H.O. 63:965-981 (1985)

PLANT-DERIVED DRUGS• Analgesics: Aspirin: Salix species/Europe

Morphine, Codeine;Papaver somniferum/Mesopotamia (Iran, Iraq)

• Cardiotonic: Digitalin: Digitalis purpurea/UK-Europe

• Malaria: Quinine: Cinchona spp./AmazoniaArtemsinin: Artemisia annua/China

• Antihypertensive: Reserpine: Rauwolfiaserpentina/India

• Memory enhancement: Physostigmine: Physostigmavenenosum/West Africa

Muscle relaxant: Tubocurarine:Chondrodendron spp./Amazonia

ANTIMALARIAL DRUGS

N

HNN

Cl

Chloroquin

N

HN

HO

CF3

CF3

Mefloquine

N

O

N

H

HHO

Quinine

Quinine from Cinchona spp. used in the Amazon region for centuries for treatment of fevers.

TREATMENTS FOR DRUG RESISTANT MALARIA

O

O H

HO O

O

H

Artemisinin

O

O H

HO O

Artemether R = CH3Arteether R = CH2CH3

OR

H

Artemsia annua used in TCM for centuries for treatment of fever.

Discovery of Lidocaine

• Central Asian camels refused to eat a certain type of reed, Arundo donax

• Characterization of gramine as the antifeedantprinciple led to the synthesis of isogramine(taste-test: numbness)

Lidocaine (xylocaine)

gramine

NH

NMe

Me

Isogramine

NMe

Me

NH

57 synthetic derivatives(followed by taste test)

NNH

OMe Me

Me

PLANT-DERIVED ANTICANCER DRUGS

IN CLINICAL USE OR DEVELOPMENT• Vinblastine/Vincristine: Catharanthus roseus/Jamaica,

Philippines (originally from Madagascar)

• Etoposide: Podophyllum species/ Eastern US, Himalayas

• Paclitaxel/Docetaxel: Taxus species/NW US, Europe

• Topotecan/Irinotecan: Camptotheca acuminata/China

• Homoharringtonine: Cephalotaxus harringtonia/China

• Flavopiridol: Synthetic based on rohutikine fromDysoxylum binectariferum/India

• Combretastatins: Combretum caffrum/S. Africa

Indigofera tinctoriaIsatis indigotia

Qing Dai: Used in TCMfor treatment of myelocytic leukemia.

Source of indirubin: CDKinhibitor.

Indirubin Derivatives

NH

NH

R2

O

R1

Indirubin R1 = H R2 = O R3 = H Indirubin-3'-monooxime R1 = H R2 = N-OH R3 = H Indirubin-5-sulphonic acid R1 = H R2 = O R3 = SO3H

R3

Derivatives show selective activity against CDK1

INTERNATIONAL COLLABORATION

• Prior informed consent/permits from Source CountryGovernment and stakeholders.

• Collaboration with Source Country Organizations.• Training and technology transfer.• Protection of environment and sustainable development.• Plans for benefit-sharing

Dr. D. SoejartoU. Illinois at Chicago

The late Don Eligio Panti, traditional healer from Belize, receiving Certificate of Recognition for services to

New York Botanical Garden in their collection program for the National Cancer Institute

The late Don Eligio Panti consulting in Belize

TRADITIONAL HEALER. WESTERN SAMOA

Dr. Paul Cox, National Tropical Botanical Garden

CONTRIBUTION OF SAMOAN TRADITIONAL HEALERSPOTENTIAL ANTI-HIV DRUG FROM HOMALANTHUS NUTANS

P.A.Cox, Pharmaceutical Biology, 2001, 39 (Supplement ), 33-40

PROSTRATIN

Potent activator of HIV

expression in latently-

infected T-cells

PROSTRATIN

Licensed by NIH to the AIDS ReSearchAlliance of America.Agreement with Government of Samoa.Milestone payments on completion ofPhase I, II and III clinical trials.Royalties totaling 20% of net revenues.

D.D. Soejarto, University of Illinois at Chicago

Calophyllum teysmannii var. inophylloide. Sustainable source of potential anti-AIDSdrug, calanolide B. Discovery from tree in Sarawak, Malaysia, promoted conservation and replanting of seedlings in clearcutregions, and led to establishment of theSarawak Biodiversity Center for in-countryresearch on drug discovery from local biodiversity

O

O O O

OH

O

O O O

OH

(+) - Calanolide A (-) - Calanolide B

CALANOLIDESDEVELOPMENT

1995: Calanolides licensed to Medichem Research Inc.

Synthesis of (+)-calanolide A supported by NCI SBIR grant

Negotiation with Sarawak State Govt. required by LOC1996: Joint venture company, Sarawak MedichemPharmaceuticals formed

Phase I trials of Calanolide-A completed/well tolerated

Phase II trials in progress

Calanolide B in preclinical development

NCI MEMORANDUM OF UNDERSTANDING

Agreements with qualified Source Country Organizations.

SCO performs collections, extractions, prescreening andbioassay-guided fractionation in-country at own expense.

NCI assists SCO to establish screening facility throughprovision of training and cell lines at NCI expense.

NCI provides free secondary in vitro and in vivo testingwith no IPR claims.

SCO applies for appropriate patent coverage.

NCI collaborates in development of SCO drugs meetingNCI selection criteria – at NCI expense

NCI MEMORANDUM OF UNDERSTANDING

MOUs have been signed with organizations in the followingcountries:

Australia, Bangladesh, Brazil (5), China (3), Costa Rica,

Fiji, Iceland, Korea, Mexico, New Zealand, Nicaragua,

Pakistan, Papua New Guinea, Panama, South Africa (2),

Zimbabwe

Studies on Anticancer Drug Discovery and

Development from Brazilian Biodiversity

Laboratory of Experimental Oncology– LOEClinical Pharmacology Unit - UNIFAC

Department of Physiology and PharmacologyFederal University of Ceará

www.loe.ufc.br

Ceará

LOELOENUBBE- UNESP

Araraquara - São PauloDra. Vanderlan Bolzani

National Research Institute of Amazonia (INPA) - Amazonas

Dr. Adrian Pohlit

USP- Pharmacy School of Ribeirão Preto (USP - São Paulo)

Dr. Noberto Peporine

Depart. of Organic Chemistry (UFC) Dr. Edilberto Silveira, Telma Lemos

and Otilia Pessoa

Chemistry Institute of São Carlos (USP - São Paulo)

Dr. Roberto Gomes Berlinck

MOU between UFC and National Cancer Institute

Clinical Pharmacology UnitFederal University of Ceara-UFC

Dra. Maria Elisabete Moraes

Institute of Marine Sciences -(UFC)Dr. Tito Lotufo

Natural Product Laboratory-UFLA - Minas GeraisDr. Denilson Oliveira

Bioorganic & Medicinal Chemistry -UCB - BrasíliaDr. Luis Antonio Romeiro

Natural Resource Laboratory-UFAL - Alagoas

Dr. Euzebio Sant Anna

Prisco Bezerra Herbarium (UFC)Dra. Francisca Cavalcanti

Amazon rain forestAtlantic forestAraucaria forestCerrado (Scrub)Caatinga (Semi-arid)FieldsPantanal (Swamp)Dunes and Mangrove

Brazilian Ecosystem

AFASSA: Africa, Asia and South America

• Co-ordinates activities of networks involved in natural productresearch in Africa, Asia and South America.

• Founded at ntercontinental Symposium on Natural ProductsResearch in Montevideo in December, 1999.

• Chairmanship of Dr Federico Dajas, Clemente Estable Institute,Montevideo University, Uruguay

NAPRECA SYMPOSIUMADDIS ABABA 2003

Drug Sources

B9%

N14%

ND26%

S36%

S*14%

V1%

B

N

ND

S

S*

V

Newman et al., J. Nat. Prod. 66:1022 (2003)

Antibacterial 79%; Anticancer 62%; Antihypertensive 74%; Antimigraine 70%

WHAT ARE WE LOSING!

CLEAR-CUTTING AND SLASH AND BURN DESTROYS NOT ONLY THE TREES AND MACRO-FAUNA BUT MUCH OF THE ASSOCIATED MICRO-FAUNA AND MICROBIALLIFE – AN INVALUABLE ANDIRREPLACABLE RESOURCE.

THANK YOUhttp://dtp.nci.nih.gov