RASOANAIVO Organic synthesis

Organic synthesis
ICSN Worldwide Collaborations

Background Gif connection

ICSN
Madagascar
Cape Town
Lille, Montpellier,
Others

Muséum NHN
INSERM

The ICSN World-Wide Collaborations
Integrated approach to
ethnobotany-directed screening
Philippe Rasoanaivo

Institut Malgache de Recherches Appliquées

Ethnic group
Ecosystem

Environment

Ethnobotany

Plants

Culture
► medical (health, foods)
► Functional
► Cultural
► Cognitive

1985’s

Severe malaria epidemics in
The Highlands of Madagascar

New disease
(Bemangovitra)

New treatments
(Chloroquine + plants )
P. Rasoanaivo, A. Petitjean, S. Ratsimamanga, A. Rakoto-Ratsimamanga.
J. Ethnopharmacol. 1992; 37: 117-127.

Medicinal plants used to potentise chloroquine action

Strychnos diplotricha
Strychnos myrtoides

Strychnos mostueoides

Hazomalania voyroni

Strychnopsis thouarsii
Spirospermum penduliflorum
Burasaia madagascarienis

OCH3

H3CO

N
H3C

N

OCH3
H

CH3

O

H

O
OCH3

Limacin
Spirospermum penduliflorum
OCH3

H3CO

N
H3C

N

OCH3
H

CH3

O

H

O
OCH3

Fangchinolin
Strychnopsis thouarsii
S. Ratsimamanga, P. Rasoanaivo, H. Rafatro, et al. Planta Med. 1992; 58:540-3

MeO

OMe
N

Me

MeO

7

O

OR1

MeO
N

CH3

12'
R2O

Hazomalania voyroni

Hervelines

● P. Rasoanaivo, S. Rasimamanga-Urverg, C. Galeffi, M. Nicoletti, F. Frappier,
M-T. Martin. Tetrahedron 1995, 51, 1221-8.
● P. Rasoanaivo, S. Ratsimamanga-Urverg, H. Rafatro, D. Ramanitrahasimbola
et al. Planta Med. 1998; 64: 58-62.

N
3

H
CO2CH3

N
Ac

Strychnos myrtoides

CH3

H
O

Malagashanine
O

S. mostueoides

N

CH3

N

S. diplotricha
Ac

O

CH3

Strychnobrasiline

Malagashanine derivatives
N
3

12

R

N
Ac

CH3
N

H
CO2CH3

H

N

19

Ac

O

12-hydroxy-malagashanine
19-epi-malagashanine

R1

Ac

CH2OH
H
O

CH3
H

3

N

H

Malagashanol

N

R2

CH

3

O
O

H
O

Myrtoïdine series

● M.-T. Martin, P. Rasoanaivo, G. Palazzino et al.. Phytochemistry, 51, 479 (1999).
● P. Rasoanaivo, G. Palazzino et al. (2001) Phytochemistry, 56, 863 (2001).

Integrated approach
Screeningto
of antimalarial plants
Plants + CQ
Antiplasmodial plants

Chemosensitisers
True antimalarials

Cytotoxicity
Preventive plants

Prophylactic

Hepatic stage of malaria parasite

Research Initiative on
Traditional Antimalarial Methods
(RITAM)

New morphinan alkaloid
Strychnopsis thouarsii
in vitro & in vivo schizontocidal activity
in the hepatic stage

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
N

CH3

N
Ac

O

CH3

Strychnobrasiline

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

O

CH3

CH3

N
N

CO2CH3

N

Ac

O

CH3

O

Strychnobrasiline
N

CH3
N

H

CO2CH3

N
O

CH3

CO2CH3

N
O

F. Trigalo, R. Joyeau, V. C. Pham, J. J. Youté, P. Rasoanaivo, F. Frappier.
Tetrahedron 2004, 60, 5471-4.

Malagashanine as a source of inspiration
CH3

CH3

N

N

N

CO2CH3

N

N

Desipramine

Ac

N
H

O

Me

CH3

Me

CH3

N

N

N

H
N

CO2CH3
N

N

Cl

Ac
O

Ac

Chlorpheniramine

Pervilleine series
OCH3

H3CO

OCH3
CH3
N
O
O
OCH3
OCH3

O
O

OCH3

Erythroxulym pervillei

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.

Pervilleine series and verapamil
OCH3

H3CO

OCH3

OCH3

H3CO

CH3
N
CN

O
O
OCH3
OCH3

O
N

H3CO

CH3

OCH3

Verapamil

O

OCH3

Basic requirements for
Chemosensitizing pharmacophores

S

(C)n

S ~ S’ = N, aromatic

Synthesis ?

S’

Chibale’s team, Cape Town
Br

X
N

X = N, O

O

HN

F. Chouteau, D. Ramanitrahasimbola, P. Rasoanaivo, K. Chibale.
Bioog. Med. Chem. Lett. 2005 (in press).

N

Chemosensitizing pharmacophore and polyamines
NH2

H2N

Putrescine
H2N

N
H

NH2

Spermidine
CH3

NC
H3CO

N

OCH3

Verapamil

H3CO

OCH3

CH3
OCH3

OCH3

N

CH3
OCH3

OCH3

H3CO

OCH3

N

OCH3

H3CO

O

H3CO

O

OCH3

O

H3CO

O

Pervilleine C

H2N

O

O

O

O

H
N

Spermine

N
H

OCH3

NH2

Chloroquine with modified side chains
N

CH3

OMe
OMe

CO2CH3

N
Ac

(C)n

O

OMe

O

HN

Cl

N

N

D. Ramanitrahasimbola, P. Rasoanaivo, S. Ratsimamanga, H. Vial.
Mol. Biochem. Parasitol. 2005 (in press).

The “isolated organs” programme

London, 2002

O

Coumarin
Phymatodes scolopendria
D. Ramanitrahasimbola, D. Rakotondramanana, P. Rasoanaivo , et al.,
J. Ethnopharmacol. 2005 (in press).

O

HO

Buddleya madagascariensis

Embelia concinna

HO

O

O

Ravenala madagascariensis
O
O

Helichrysum species and inflammation
50 µg EtOAC extract
96% NFκB inhibition
No cytotoxicity
98% HIV replication inhibition

Helichrysum cordifolium

Integrated approach for the screening of plants
used in the treatment of vascular or pulmonary disorders
Plants
Anti-inflammatory

Vaso-relaxing

Broncho-relaxing

+
NFκB
+
Anti-HIV

Mechanism of action

The way forward
ICSN – Madagascar project on bioprospecting

March 2005

Two former ICSN phytochemists

Annual NMR training through ICSN support

Year 2000, Madagascar

Acknowledgements
Agence Universitaire de la Francophonie
CAMPUS/CORUS
PAl+
IFS grants
Pharmaceutical industries
CNRS bioprospecting project