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THE MADAGASCAR
INTERNATIONAL COOPERATIVE
BIODIVERSITY GROUP:
BACKGROUND AND HISTORY
David Kingston
Department of Chemistry
Virginia Polytechnic Institute & State University
Web: 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
 Natural
6%
26%
59%
9%
Product Drugs
 Modified Natural Product Drugs
 Synthetic Drugs Based on Natural Product Models
 Synthetic Drugs
MORE REASONS FOR FAITH IN NATURAL
PRODUCTS
2580
# of issued patents
microbial
plant
2000
total
NP are more diverse than synthetics
Synthetic Compound from
combinatorial chemistry
Chiral
ctr = 0.4
1153
969
1000
Natural Products
Chiral ctr = 6.2
694
448
315
165
50
91
0
1986-1990
1991-1995
1996-2001
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
Drugs
Chiral
ctr =
2.3
Feher and Schmidt 2003 J
Chem Inf Comput Sci 43:218
SOME IMPORTANT ANTICANCER NATURAL
PRODUCTS
TAXOL, from Taxus brevifolia
AcO
O
C6H5
NH
O
O
2
O
OH
7
10
13
C6H5
OH
HO
O
H
OAc
OCOC6H5
■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 LIBRARIES
R. Breinbauer et al, Angew. Chem. Int. Ed. 2002, 41, 2878
EXAMPLE: THE HALICHONDRINS
M. J. Yu 224th ACS National Meeting, Boston, MA, August
21, 2001, Abstract MEDI 238.
H
H
H
O
O
H
O
O
H
HO
H
H
H
O
O
O
O
HO
H
O
O
H
H
O
H
H
O
O
O
HO
O
O
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 CONSERVATION
CARRY 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
CONSERVATION
CENTRE 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
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 region
Approximately 80% of species
are endemic
Great ecosystem diversity
Work is urgent, since much of
the country has been deforested
MADAGASCAR
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 KEEPING
ECOTOURISM INITIATIVE
IMPROVED CROPS
INFRASTRUCTURE IMPROVEMENTS
USING UPFRONT COMPENSATION
FUNDS IN THE SAME VILLAGES
AGRICULTURAL WAREHOUSE
RENOVATION OF A PRIMARY SCHOOL
CONSTRUCTION OF A FOOTBRIDGE