ANTICANCER AND ANTI-HIV DRUGS DERIVED FROMAFRICAN AND OTHER PLANTS

Gordon Cragg, Ph.D. NIH Special Volunteer

Natural Products BranchDevelopmental Therapeutics Program

Division of Cancer Treatment and Diagnosis

NCI-Frederick Fairview Center, Suite 206

P. O. Box B Frederick, 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

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./Amazonia Artemsinin: Artemisia annua/China

• Antihypertensive: Reserpine: Rauwolfia serpentina/India

• Memory enhancement: Physostigmine: Physostigma venenosum/West Africa

Muscle relaxant: Tubocurarine:Chondrodendron spp./ Amazonia

Epothilone A docked in tubulin active site

O

O

HO

O OOH

N

S

6

11 13

15

Epothilone AIsolated from glidingbacteria (Myxobacteria)

NATURE – THE SUPREME MOLECULAR ARCHITECT!

Nettles et al., "The Binding Mode of Epothilone A on a,ß-Tubulin by Electron Crystallography" Science, 6 August 2004, Vol. 305, pp. 866-869 (Copyright AAAS)

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 from Dysoxylum binectariferum/India

• Combretastatins: Combretum caffrum/S. Africa

INTERNATIONAL COLLABORATION

• Prior informed consent/permits from Source Country Government 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

MICHELLAMINE BPotential Anti-AIDS Agent

Discovery and Development

• 1987: Collected liana Ancistrocladus korupensis leaves. Korup National Park, Mundemba, S. West Cameroon. Dr. Duncan Thomas (MBG) and Mr. Ndembe (Forestry Dept.).

• New species (Thomas & Gereau, Novon, 1993, 3, 494-498).

• 1989: Michellamine B isolated. Active against a range of HIV-1 and HIV-2 strains (Boyd et al., J. Med. Chem, 1994, 37, 1740-45).

• Sufficient isolated from fallen leaves for preclinical development.

MICHELLAMINE B COLLABORATION: CAMEROON

FEASIBILITY STUDYCULTIVATION OF A. KORUPENSIS

U n ive rs ity o fY ao un de

Jo hn son Ja to

W o rld W ild lifeF u nd

P a u l S ym o n ds

M isso u riB o tan ica lG a rd en

Ja m e s M ille r

O reg on S ta teU n ive rs ity

D u n ca n T ho m as

P u rd u e U n ive rs ityC e n te r fo r N e w C ro ps a n d P la n t P rod u c ts

Ja m e s S im on

N a tion a l C a n ce r In stitu teG o rdo n C ra gg

A. KORUPENSIS CULTIVATION STUDIES

• 1993: Contract for cultivation feasibility study awarded.

• All studies performed in Korup region involving local population.

• Extensive botanical and analytical survey: - Distribution: One liana per hectare.- Dried leaf analysis (N=>1,000): Up to 4% (w/w) MB.

• Nursery established at Mundemba. Cuttings of high-yielding plants propagated. • MB content of 1,5 year old seedlings: 0.07-0.73%

DEVELOPMENT OF MICHELLAMINE B

• Formulation as diacetate salt.

• Toxicology: Rodents, dogs, primates.

Toxic dose level close to anticipated effectiveantiviral dose (narrow therapeutic index).

• Development suspended.

• Possibility of lead development (Bringmann, Wurzburg).

• Novel antimalarial agents, the korupensamines, add further promise for A. korupensis.

POTENTIAL ANTI-HIV DRUG FROM HOMALANTHUS NUTANS : PROSTRATIN

• Dr. Paul Cox entered into a Covenant with healers of Western Samoan village of Falealupo

• Covenant signed with village chiefs and orators with concurrence of Prime Minister and Parliament.

•Use of Homalanthus nutans by healers recorded by Dr. Cox: Treatment of “yellow” fever.

• $480,000 provided for schools, clinics, water supplies, trails, aerial walkways, etc.

• Endowment established for preservation of forest. P.A.Cox, Pharmaceutical Biology, 2001, 39 (Supplement ), 33-40

Samoan Traditional Healers in Village of Falealupo

Potent activator of HIV

expression in latently-

infected T-cells

• Licensed by NIH to the AIDS ReSearch Alliance of America

• Agreement with Government of Samoa

• Milestone payments on completion of Phase I, II and III clinical trials

• Royalties totaling 20% of net revenues

• Distribution between government, village community and healers’ families

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 clearcut regions, 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

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

CALANOLIDES DEVELOPMENT

1995: Calanolides licensed to Medichem Research Inc.

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

Negotiation with Sarawak State Govt. required by LOC 1996: Joint venture company, Sarawak Medichem Pharmaceuticals formed

Phase I trials of Calanolide-A completed/well tolerated

Phase II trials in progress

Calanolide B in preclinical development

PARALLEL DEVELOPMENT OF HERBAL MEDICINES AND THE DISCOVERY OF

NOVEL CONVENTIONAL DRUGS

Bioassay-guided isolation and chemical characterization

of active principle(s)

• Provide markers for standardization of herbal products

• Provide lead compounds for conventional drug

development

Basic Philosophy

Any herbal drug or botanical supplement to be considered for clinical trials must be botanically authenticated as well as chemically and biologically standardized.

Dr. Norman Farnsworth, Director, UIC/NIH Center for Botanical Dietary Supplements Research

Steps Required Prior to Clinical Assessment of Herbal Drugs/Botanical Dietary Supplements

1. Acquire plant material

• Verify identity; taxonomic/microscopic/PCR

• Check for pesticides; herbicides; heavy metals

2. Establish/select appropriate bioassay

3. Bioassay several types of extracts

• In vitro

• In vivo (if possible/relevant)

Steps Required (continued) 4. Bioassay-guided isolation and chemical characterization of active principle(s)

5. Prepare the biologically and chemically standardized dosage form

• Conduct stability studies

6. In vitro studies on standardized product

• Metabolism (including interactions with p450s)

• Pharmacokinetics

• Toxicity

• Mechanism of Action

Thank you for visiting this website, which is intended to be a network hub for all stakeholders in Africa’s natural plant products sector. Through knowledge-sharingand information-exchange via this site, ASNAPP (Agribusiness in Sustainable Natural African Plant Products) seeks to create a knowledge community that will strengthen the continent’s capacity to develop this sector. In the interests of developing successful natural product agribusinesses, and thushelping to reduce poverty in rural communities, ASNAPP promotes collaboration and knowledge sharing with research and academic institutions, government, private enterprises, non-profit organizations, the donor community and civil Society.For this purpose, the ASNAPP website encourages information exchange in any of the following areas:

Applied research and technology transfer Quality assurance and control

Market linkages and development Enterprise and farmer association development

Natural resource management Policy dialogue and advocacy

http://www.asnapp.org/

These areas are the main thrust of ASNAPP’s activities for 2005, based on the following three new programmes funded by the United States Agency for International Development (USAID):

The Partnership for Food Industry Development Program (PFID), managed by Rutgers University’s New Use Agriculture and Natural Plants Products Program.

The Rural Livelihoods Activity in Southern Africa programme, run by the Michigan State University Partnership for Food Industry Develop Program – Fruits and Vegetables (MSU PFID – F & V) in conjunction with a consortium of partners.

The Partnership for Sustainable Germplasm Development for Non-traditional Crops, a collaborative project involving various academic and research institutions as well as private enterprises in South Africa and Zambia.

ASNAPP USARutgers University - Cook CollegeDepartment of Plant Biology and Plant Pathology59 Dudley Road, 381 Foran HallNew Brunswick, New Jersey 08901Professor Jim SimonCo-Principal Investigator and Quality Control Coordinator ASNAPP ProgramNew Use Agriculture and Natural Plants ProgramTel: +732 932-9711 Ext. 355/379Fax: +732 932-9377Email: jesimon@aesop.rutgers.eduWebsite: www.nuanpp.org     

Partner countries: Ghana, Rwanda, Senegal, South Africa, Zambia, USA

While many CAM treatments have already been in use for a long time (sometimes for centuries), there is not the kind of scientific knowledge available about them that has been gained from studies of conventional medicine. Many people are already using CAM, and without this scientific knowledge, they may be at risk— for example, for serious effects from taking the wrong dose, using the treatment in the wrong way, or using it with another treatment with which it interacts.

Clinical Trials and Complementary and Alternative Medicine (CAM)

INTERNATIONAL AND REGIONAL COLLABORATIONAFASSA: Africa, Asia and South America

• Co-ordinates activities of networks involved in natural product research in Africa, Asia and South America.• Founded at Intercontinental Symposium on Natural Products Research in Montevideo in December, 1999.

NAPRECA SYMPOSIUMADDIS ABABA 2003

Next symposium:Antananarivo, MadagascarAugust 9-12, 2005Takelaka.dts.mg/rafita

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