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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: [email protected]
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
CONTRIBUTION OF SAMOAN TRADITIONAL HEALERSPOTENTIAL ANTI-HIV DRUG FROM HOMALANTHUS NUTANS
P.A.Cox, Pharmaceutical Biology, 2001, 39 (Supplement ), 33-40
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
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.