RASOANAIVO Natural product and drug discovery

N
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11th NAPRECA Symposium

Natural Products and Drug Discovery
through a Network of Partnerships

Philippe Rasoanaivo
Chairman, Organising committee

“Eventail” of partnerships
Fr

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a

Italy

South Africa

US
A
y
as s
ag st
al ti
M ien
sc

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Ca
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Malaria Lab

Contents
► Malaria programme
► Semisynthesis/Synthesis programme
► Anti-inflammatory---antiviral pathway

In 1985’s: Sudden resurgence of malaria in the
Highlands of Madagascar

Malaria programme

Integrated approach to
antimalarial plants
Chemosensitising
True antiplasmodial
Antimalarial
plants
Cytotoxic
Prophylactic

A chemosensitizing and prophylactic plant
OCH3

H3CO

N
H3C

N

OCH3
H

CH3

O

H

O
OCH3

Fangchinolin
Strychnopsis thouarsii
(Menispermaceae)

S. Ratsimamanga, P. Rasoanaivo, D. Ramanitrahasimbola, et al.
Planta Med. 1992; 58:540-543.

Research Initiative on Traditional
Antimalarial Methods

RITAM inaugural meeting,
Moshi, December 1999

S

S
S

Strychnopsis thouarsii
N-R

OCH3

H3CO

N
H3C

N

OCH3
H

CH3

O

S

S

H

O
OCH3

Fangchinolin

S

Morphinan alkaloid
Active in vitro & in vivo

Patent N° 04291055.4, 22 April 2004.

Control mice (red), treated mice (green)
and dead mice (black dot)

60

% parasitémie

50
40
30
20
10
0
J3

J4

J5

J6

J7

J8

J9

J10 J12 J14 J16 J19 J21

Post-infection days

M. Carraz, PhD, 2005

Chemosensitizing indole alkaloids
Malagasy Strychnos: S. myrtoides, S. mostueoides, and
S. diplotricha
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
N

N

CH3

CH3

N

CO2CH3

N
O

O
H3CO

C

O
O
F. Trigalo, M. T. Martin, A. Blond, B. Rasolondratovo, P. Rasoanaivo, F. Frappier.
Tetrahedron 2002, 58, 4555-58.

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

Strychnobrasiline derivative
O

O

N

N

CH3

H

N

H
H

N
O

Ac

CH3

O

CH3

O

CH3

Fe

D. Razafimahefa, L. Pélinski, M.-T. Martin, D. Ramanitrahasimbola, P. Rasoanaivo,
J. Brocard. Bioorg. Med. Chem. Let. 2005, 15, 1239-1241.

Naturally-occurring chemosensitizers:
source of inspiration for medicinal chemistry
CH3
CH
3
NN

N
N
H

CO2CH3
N
N

Desipramine

Ac
O

Me

Me

CH3
CH
3

N

N
N

H
N
CO2CH3
NN

Cl

Ac

Ac
O

Chlorpheniramine

Pervilleine series
OCH3
H3CO

OCH3

CH3
N
HO

O

O

OCH3
OCH3
O
OCH3

Erythroxylum pervillei

O

Collaboration with the University of Illinois at Chicago

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.

OCH3
H3CO

OCH3

OCH3

H3CO

OCH3

CH3

CH3

N

N

O

HO

O

O

O

OCH3
OCH3
O

H3CO

OCH3
H3
CO

NC

O

CH3
N

CH3
N

Verapamil

OCH3

OCH3

OCH3
OCH3

O
OCH3
O

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.

Chemosensitizing pharmacophore and polyamines
NH2

H2N

Putrescine
H2N

N
H

NH2

Spermidine
CH3

NC
H3CO

N

OCH3

Verapamil

H3CO

OCH3

CH3

OCH3

OCH33
OCH

N

OCH33
OCH

H
H33CO
O

H
H33CO

O

O

Pervilleine C

H2N

OCH
OCH33
O

H
N

Spermine

N
H

NH2

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

MeO

Herveline series

OMe
N

MeO

OMe

Me

N
7

MeO

OMe

Me
7

MeO
1.00

MeO
N
CH3

MeO

Herveline A
Herveline B
Herveline C
Herveline D

O

0.80

O
N
CH3

12'

12'

MeO

0.60

MeO

HO

0.40

OMe
N

OMe

MeO

OMe

Me

N

7

MeO

OH

Me
7

MeO

0.20

MeO

OH

MeO
O

O
0.00

N
CH3

N
0.00

0.20

0.40

0.60

0.80

CH3

1.00

12'

12'

MeO

HO

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

Malagashanine as a biochemical tool
N

CH3

CO2CH3

N

HN

Cl

N

Ac

O
N

CH3

N
N
Ac

CO2CH3
H
O

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

Chloroquine with modified side chains
OH
N

N

N

HN

HN

HN

Fe
Cl

Cl

N

Chloroquine

N

Cl

Amodiaquine
O

HN
N

R1

N

Ferroquine
R2
R3

N
R4

Cl

N

Cape Town and IMRA partnership, work in progress

World malaria distribution and
occurrence of antimalarials

Artemisinin
Quinine

?

Anti-inflammatory---antiviral pathway
Baobab
Strong antiviral activities
Anti-inflammatory activities
J. B. Hudson, M. K. Lee, P. Rasoanaivo.
Pharm. Biol. 2000, 38, 36-39.

Helichrysum
Inhibition of NF-κB
Strong anti-HIV actitivities

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

Integrative approach

Partnerships