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CNR RAO Award Lecture
Natural products drug discovery
through a network of Partnerships
Philippe Rasoanaivo
Institut Malgache de Recherches Appliquées
Madagascar
Team
Multi-disciplinary
Natural products
Drug discovery
Inter-disciplinary
Trans-disciplinary
Integrated approach
N
E
T
W
O
R
K
“Eventail” of partnerships
Africa
USA
Sw
ed
en
y
as ts
ag is
al t
M ien
sc
rs
e
l
a
He
n
a
r
F
ce
Italy
IMRA
In 1980’s: Sudden resurgence of malaria in the
Highlands of Madagascar
Malaria programme on medicinal plants
Reversing agents in malaria
Bringing Traditional knowledge into
Useful applications
► Isolation of
active constituents
►Semisynthesis
Integrated
approach
►Source of inspiration for
Medicinal chemistry
►Biochemical tool
►Phytomedicine
Malagasy Strychnos and
Chemosensitizers in malaria
N
CH3
O
H
CO2CH3
N
Ac
N CH3
O
Malagashanine
Active in vitro & in vivo
N
Ac
O
CH3
Strychnobrasiline
Active in vitro but not in vivo
P. Rasoanaivo, S. Ratsimamanga, R. Milijaona, H. Rafatro, C. Galeffi,
M. Nicolleti. Planta Med. 1994, 60, 13-16.
Malagashanine derivatives
N
3
12
R
N
Ac
CH3
N
H
CO2CH3
H
N
19
Ac
O
12-hydroxy-malagashanine
19-epi-malagashanine
CH
3
H
CH2OH
H
O
Malagashanol
N
CH3
H
O
3
N
R2
R1
Ac
H
O
O
Myrtoïdine series
● M.-T. Martin, P. Rasoanaivo, G. Palazzino et al.. Phytochemistry 1999, 51, 479.
● P. Rasoanaivo, G. Palazzino et al. Phytochemistry 2001, 56, 863.
Strychnobrasiline for semisynthesis
O
O
O
N
N
CH3
CH3
N
N
O
Ac
O
O
CH3
CH3
Strychnobrasiline
CH3
N
N
O
O
H3CO
C
O
F. Trigalo, M. T. Martin, A. Blond, B. Rasolondratovo, P. Rasoanaivo, F. Frappier.
Tetrahedron 2002, 58, 4555-58.
Strychnobrasiline for semisynthesis
O
O
N
CH3
N
CH3
H
N
N
Ac
O
CH3
H
H
Strychnobrasiline
O
O
CH3
Fe
D. Razafimahefa, L. Pélinski, M.-T. Martin, D. Ramanitrahasimbola, P. Rasoanaivo,
J. Brocard. Bioorg. Med. Chem. Let. 2005, 15, 1239-1241.
Strychnobrasiline for semisynthesis
N
CH3
O
CH3
N
N
CO2CH3
N
Ac
O
CH3
O
Strychnobrasiline
N
CH3
N
H
CO2CH3
N
O
N
CH3
CO2CH3
O
F. Trigalo, R. Joyeau, V. C. Pham, J. J. Youté, P. Rasoanaivo, F. Frappier.
Tetrahedron 2004, 60, 5471-4.
Malagashanine:
source of inspiration for medicinal chemistry
CH3
N
N
CH3
N
H
N
CO2CH3
N
Desipramine
Ac
O
N
Me
Me
CH3
CH3
N
N
N
H
N
CO2CH3
N
N
Ac
Cl
Ac
O
Chlorpheniramine
Pervilleine series
OCH3
H3CO
OCH3
CH3
N
HO
O
O
OCH3
OCH3
O
OCH3
Erythroxylum pervillei
O
B. Cui, G. L. Silva, D. Chavez, M. You, H.-B. Chai, P. Rasoanaivo, S. M. Lynn, M. O’Neill, J.
A. Lewis, J. M. Besterman, A. Monks, N. R. Farnsworth, G. A. Cordell, J. M. Pezzuto,
A. D. Kinghorn. Journal of Natural Products 2001, 64(12), 1514-19.
Pervilleine series: dissecting the molecule
OCH3
H3CO
OCH3
CH3
N
HO
O
O
OCH3
OCH3
O
OCH3
O
Verapamil
Basic requirements for
Chemosensitizing pharmacophores
S
(C)n
S’
S ~ S’ = N, aromatic
Synthesis ?
P. Rasoanaivo. Proceeding of the 5th Colloquium on Plant Natural Products,
Québec, 7-9 August 2001, pp. 128-140.
Br
X
N
X = N, O
O
N
N
H
F. Chouteau, D. Ramanitrahasimbola, P. Rasoanaivo, K. Chibale.
Bioog. Med. Chem. Lett. 2005, 15, 3024-28.
One relevant result
10 nM
l
a
i
d
o
m
s
a
l
ip
t
n
A
Ch
em
os
en
sit
izi
n
g
Malagashanine as a biochemical tool
N
CH3
CO2CH3
N
HN
Cl
N
Ac
O
N
CH3
N
N
Ac
CO2CH3
H
O
Bi-directional, reversible
Chloroquine transporter in malaria
CQ
D. Ramanitrahasimbola, P. Rasoanaivo, S. Ratsimamanga, H. Vial.
Mol. Biochem. Parasitol. 2006, 146, 58-67.
Standardized Phytomedicine
Placebo controlled,
double blind clinical trial
Aqueous extract
Clinical observational studies
A. Ramialiarisoa, J. Ranaivoravo, P. Rasoanaivo, S. Ratsimamanga.,
Rév. Méd. Pharm. Afr. 1994, 8, 123.
Research Initiative on Traditional
Antimalarial Methods (RITAM)
RITAM inaugural meeting,
Moshi, December 1999
Hepatic stage of malaria parasites
H3CO
10
HO
OH
NH
HO
OCH3
OH
Strychnopsis thouarsii
Tazopsine
M. Carraz, A. Jossang, JF Franetich, A. Siau, L. Ciceron, F. Frappier,
P. Rasoanaivo, G. Snounou, D. Mazier, PLoS Medicine 2006 (in press).
World malaria distribution and
occurrence of antimalarials
Artemisinin
Quinine
?
Chronic degenerative diseases
SA Pharmacology Meeting, 2003
Ageing ~ Resistance
Advanced Glycation End-products
Chronic degenerative diseases
Integrated
approach
►Diabetes
Cardiovascular and
Erectile disorders
► Memory impairment
CNRS-funded bioprospecting
Extract library
Structure diversity
Antimalarial
Cytotoxicity
Antibacterial
Broad screening
Research & Teaching in an
integrated approach
Networking
Acknowledgments
The Government of Brazil
The Academy of Sciences of the Third World
The Brazilian Academy of Sciences
The C.N.R. RAO Prize