THE MADAGASCAR INTERNATIONAL

COOPERATIVE BIODIVERSITY GROUP:

BACKGROUND AND HISTORY

David Kingston Department of Chemistry

Virginia Polytechnic Institute & State UniversityWeb: www .kingston.chem.vt.edu

Natural Products as Drugs and Drug Leads

WHO estimates that ~80% of the world’s population use traditional medicine.

Between 1983 and 1994 41% of new approved drugs had natural products as their source.

David J. Newman, et al. Nat. Prod. Rep., 2000, 17, 215-234

Gordon M. Cragg, et al. J. Nat. Prod., 1997, 60, 52-60

6%

26%

9%

59%

Natural Product Drugs Modified Natural Product Drugs Synthetic Drugs Based on Natural Product Models Synthetic Drugs

1986-1990 1991-1995 1996-20010

1000

2000

# of

issu

ed p

aten

ts

microbial

plant

total

694

16550 91

315

1153

448

969

2580

MORE REASONS FOR FAITH IN NATURAL PRODUCTS

61% of all the new drugs introduced Worldwide during 1981-2002 can be traced to or were inspired by Natural Products. Newman, Cragg, Snader 2003 J Nat Prod 66:1022

Synthetic Compound from combinatorial chemistry

Natural Products

Drugs

Feher and Schmidt 2003 J Chem Inf Comput Sci 43:218

Chiral ctr = 0.4

Chiral ctr = 6.2

Chiral ctr = 2.3

NP are more diverse than synthetics

SOME IMPORTANT ANTICANCER NATURAL PRODUCTS

TAXOL, from Taxus brevifolia

O

OH

HHO

OCOC6H5

AcO

O

O

O

C6H5

NH

OH

C6H5

O

OAc

13

107

2

■Treatment for ovarian and breast cancer■Also used in stents to prevent restenosis■Major drug, with sales of over one billion dollars/year

WHY NATURAL PRODUCTS?

NATURAL PRODUCTS CAN FORM THE BASIS OF NEW COMPOUND LIBRARIESR. Breinbauer et al, Angew. Chem. Int. Ed. 2002, 41, 2878

EXAMPLE: THE HALICHONDRINSM. J. Yu 224th ACS National Meeting, Boston, MA, August 21, 2001, Abstract MEDI 238.

O

O

O

O

O

O

OO

O

OO

O

OO

O

O

HO

HO

HO

H

H

H

H

H H

H H

H

H

H

H

H

DRUG DISCOVERY THROUGH NATURAL PRODUCTS

COLLECT LARGE NUMBERS OF PLANT, MARINE, OR MICROBIAL SPECIES

PREPARE EXTRACTS AND TEST IN RELEVANT BIOASSAY SYSTEMS

RECOLLECT OR REFERMENT ACTIVE SPECIES AND ISOLATE ACTIVE COMPOUNDS BY A BIOASSAY-DIRECTED FRACTIONATION

DETERMINE STRUCTURES OF BIOACTIVE COMPOUNDS

CARRY OUT ADDITIONAL BIOLOGICAL TESTING

THE PROBLEM OF BIODIVERSITY LOSS

DRUG DISCOVERY REQUIRES RANDOM SCREENING OF THOUSANDS OF SPECIES “YOU HAVE TO KISS A LOT OF FROGS TO FIND A PRINCE”

TROPICAL RAINFORESTS COVER ONLY 8% OF THE EARTH’S SURFACE BUT HOLD 50% OF ITS PLANTS

TROPICAL FORESTS ARE DISAPPEARING FAST; DOWN FROM 16% OF EARTH’S LAND SURFACE IN 1950 TO LESS THAN 8% TODAY

TROPICAL REEFS ARE ALSO UNDER THREAT

LOSS OF RAINFOREST MEANS THE POTENTIAL LOSS OF CURES FOR CANCER, AIDS, ETC.

Brazil Vegetation 1960

Brazil Brazil Vegetation 1988

THE MADAGASCAR ICBG APPROACH TO BIODIVERSITY CONSERVATIONCARRY OUT BIOPROSPECTING WITH

FULL INFORMED CONSENT OF ALL PARTIES

PARTNER WITH PHARMACEUTICAL AND AGROCHEMICAL COMPANIES

SINCE BIODIVERSITY LOSS IS CLOSELY ASSOCIATED WITH POVERTY, COMBINE BIOPROSPECTING WITH ECONOMIC DEVELOPMENT ACTIVITIES

COMMIT TO RETURN ANY ROYALTY PAYMENTS IN PART TO THE HOST COUNTRY IN COMPENSATION FOR USE OF ITS BIODIVERSITY

HOW AND WHERE TO DO THIS?

1992 NATIONAL INSTITUTES OF HEALTH INVITED SCIENTISTS TO COMPETE FOR FUNDS TO DO DRUG DISCOVERY AND BIODIVERSITY CONSERVATION

1993-1998 VIRGINIA TECH PROPOSAL FUNDED TO DO WORK IN SURINAME

1998-2003 RENEWAL PROPOSAL FUNDED TO DO WORK IN SURINAME AND MADAGASCAR

2003-2008 THIRD ROUND OF FUNDING AWARDED FOR WORK IN MADAGASCAR

MADAGASCAR GROUP STRUCTURE VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY

CENTRAL OPERATIONS OFFICE MISSOURI BOTANICAL GARDEN

BOTANICAL COLLECTIONS, BIODIVERSITY SURVEY CONSERVATION INTERNATIONAL

ECONOMIC DEVELOPMENT, BIODIVERSITY CONSERVATIONCENTRE NATIONAL D’APPLICATION ET DES RECHERCHES PHARMACEUTIQUES PLANT EXTRACTS, ANTIMALARIAL FRACTIONATION

CENTRE NATIONAL DE RECHERCHES SUR L’ENVIRONNEMENT MARINE COLLECTION, MICROBIAL ISOLATIONS

EISAI RESEARCH INSTITUTE BIOASSAY, DRUG DISCOVERY AND DEVELOPMENT

DOW AGROSCIENCES AGROCHEMICAL DISCOVERY AND DEVELOPMENT

VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY BIOASSAY AND ANTICANCER DRUG DISCOVERY

GOALS OF THE MADAGASCAR ICBG PROGRAM

TO INTEGRATE THE PROCESS OF DRUG AND AGROCHEMICAL DISCOVERY FROM NATURAL PRODUCTS WITH CONSERVATION OF BIODIVERSITY AND SUSTAINABLE ECONOMIC DEVELOPMENT, WHILE PROVIDING FINANCIAL BENEFITS TO MADAGASCAR AND ITS PEOPLE

MADAGASCAR

WHY MADAGASCAR?

Madagascar is a prime source of biodiversity. Madagascar is one of the highest priority “Biodiversity Hotspots”Home to 25% of the plant species in the African regionApproximately 80% of species are endemicGreat ecosystem diversityWork is urgent, since much of the country has been deforested

SCIENTIFIC DEVELOPMENT IN MADAGASCAR

Laboratories at CNARP have been equipped to prepare plant extracts

Laboratories at CNARP have been equipped and personnel trained to carry out antimalarial bioassays

Facilities at CNRO (Nosy be) are being equipped to carry out marine collections

Personnel at CNRE will be trained in microbial isolations

Data handling infrastructure has been expanded

ECONOMIC DEVELOPMENT IN MADAGASCAR

SMALL-SCALE ECONOMIC DEVELOPMENT PROJECTS IN THE VILLAGES AROUND ZAHAMENA PARK, SITE OF 1998-2003 COLLECTIONS

BEE KEEPING

ECOTOURISM INITIATIVE

IMPROVED CROPS

ECONOMIC DEVELOPMENT IN MADAGASCAR

SMALL-SCALE ECONOMIC DEVELOPMENT PROJECTS IN THE VILLAGES AROUND ZAHAMENA PARK, SITE OF 1998-2003 COLLECTIONS

BEE KEEPINGECOTOURISM INITIATIVEIMPROVED CROPS

INFRASTRUCTURE IMPROVEMENTS USING UPFRONT COMPENSATION FUNDS IN THE SAME VILLAGES

AGRICULTURAL WAREHOUSERENOVATION OF A PRIMARY SCHOOLCONSTRUCTION OF A FOOTBRIDGE