RASOANAIVO drug discovery in Madagascar .pdf



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12th NAPRECA Symposium
Drug Discovery from African Flora
23- 26 July 2007
Kampala, Uganda

Recent results in plants-based
drug discovery in Madagascar

Philippe Rasoanaivo
Biotherapeutics Laboratory
Institut Malgache de Recherches Appliquées

Random drug discovery
HTS
Random screen
In vitro molecular tests
In vitro tissue/cell tests

Combinatorial chemistry
Medicinal chemistry

Biology

Chemistry

Bioinformatics

Drug design
Rational drug discovery

Drug bio-discovery
Biology

Chemistry

Environment
Man, primates Species diversity

Ethno-based
screening

Random screen
HTS

Biodiversity‐based approach
(i) In vitro molecular screening
(ii) In vitro cellular screening:
‐ Cytotoxicty, Malaria.
(Collaboration ICSN/CNRS (France – Madagascar)

Ethnobotany‐based approach
In vivo models:
‐ Malaria (blood and liver stages),
‐ Diabetes and its complications.

Areas of collecting

Plant processing & testing
Making specimens
Collecting
Drying
Grinding
Extracting
Removing tannins
Testing

Upstream of a bioprospecting program
Collection of voucher specimens
Plant library
(1-5 kg of powdered plant part)
Extract library
(2-10 g for each extract)
Tannin-free extracts
(30-40 mg)

ICSN/CNRS delegates and Malagasy team
Collecting plants in the rainforest

Drug discovery program

Patentable results

Secrecy, Confidentiality

Molecular screening for anticancer drugs
ecteinascidin 743

wortmannin
caffeine

fumagillin,TNP-470
PRIMA-1, pifithrin α

UCN-01, SB-218078
debromohymenialdisine
nitrogen mustards
isogranulatimide
nitrosoureas
mitomycin C
menadione (K3)
p53/MDM2
hydroxyurea
(R)-roscovitine (CYC202)
ATM/ATR
cytarabine
paullones, indirubins
Chk1
nucleotide excision
Chk2
antifolates
Vinca alkaloids*
repair
Plk1
5-fluorouracil
DNA synthesis
PD0166285 taxol/taxotere
G2
6-mercaptopurine
halichondrin*
CDC25
HMGA
FK317
S
spongistatin*
CDK1 Wee1
camptothecin
rhizoxin*
topoisomerase I
Aurora
Pin1
cryptophycin
tubulin
podophyllotoxin,doxorubicin topoisomerase II
M polymerisation/
sarcodictyin
etoposide, mitoxantrone
CDK2
eleutherobin
depolymerisation
Cdc7
(R)-roscovitine (CYC202)
epothilones
kinesin Eg5
CDK4
paullones, indirubins
discodermolide
ODC/SAMDc
actin
D-24851 ?
G1
GSK-3
flavopiridol
Pin1
dolastatin*
AhR
monastrol combretastatin*
polyamine analogues
MEK1/Erk-1/2
G0
cytochalasins
Raf
paullones, indirubins
ROCK
latrunculin A
farnesyl transferase
DF203
scytophycins
tyrosine kinases
PD98059, U0126
dolastatin 11
proteasome
PS-341
BAY-43-9006
jasplakinolide
choline kinase
CT-2584
YmTOR/FRAP
rapamycin
R115777
gleevec
27632
bryostatin, PKC412
PKC
SCH66336 iressa
HSP90
geldanamycin, 17-AAG
OSI774
cytosolic phospholipase A2
ATK, MAFP
histone deacetylase
trichostatin, FK228
phospholipase D
hexadecylphosphocholine
phosphatases
okadaic acid, fostreicin, calyculin A

Results of the molecular screening
~ 500 extracts screened
► 0 active extract on kinase GSK-3
(Cancer)
► 3 active extracts on kinase DIRK1A
(Alzheimer disease)
► 0 active extract on AChE
(Alzheimer disease)

Results of the cellular screening
~ 500 extracts screened
► 7 cytotoxic plants against KB ⁄ P388
cancerous cell lines


8 plants selectively active in vitro
against Plasmodium parasites

Cytotoxic compounds
OH

O

O
HO

O

O

O

O

IC50 = 0.12 µg/ml

O

HO
O

O

O

?

IC50 = 1.04 µg/ml

HO

IC50 = 0.25 µg/ml

Ethnobotany-oriented approach
Nature has created diseases and also 
cures for the diseases (G. Svoboda)
Complex, molecular,
pleiotropic diseases

multi‐component, 
multi‐functional 
therapies

Multi-component
botanical therapeutics

Malaria: a complex disease

OCH3

H3CO

N
H3C

1

N

OCH3
1'

O

CH3

O
OCH3

Limacine & fangchinoline

Strychnopsis thouarsii
S. Ratsimamanga, et al.(1992) In vitro antimalarial activities and chloroquine
potentiating action of BBIQ from Strychnopsis thouarsii and Spirospermum
penduliflorum, Planta Med., 58, 485.

The hepatic stage of malaria parasite
H 3CO

10

HO

OH

NH

HO

µM

OCH3
OH

nM

Tazopsine

Strychnopsis thouarsii
M. Carraz, et al. (2006) A plant-derived morphinan as a novel lead compound active
against malaria liver stages, PLoS Medicine, 3(12), 2392-2402.

Diabetes

Low insulin release
Insulin resistance

Complications
Cardiovascular diseases
Erectile dysfunction
Neuropathy
Retinopathy
Etc.

Diabetes
Complications:
Cardiovascular diseases
Erectile dysfunction
Neuropathy
Retinopathy
Etc.

Multi-chemical
components
Medicinal plant

Retrospective treatment outcomes (RTO)
Reverse pharmacology

Aqueous extract
Sephadex G25

Hydrophilic fraction

Active in vivo

Enzymatic
hydrolysis

Lipophilic fraction
Single active
compounds

Several factors influence the efficacy of
botanicals
- Ecological factors (mycorrhizas)
- Water composition
- Plant processing

Plant II

Plant I
“The most active compound found doesn't necessarily account
for the major part of the effect”.

Complementarities

Example of malaria

In vitro tests

If active

In vivo tests

Bioassay-guided fractionation
(project for funding)

Role of gallic acid in the in vitro
antiplasmodial activities
IC50 = 0.8 µM

OH
HO

O
3
5

O
H

O

H

H

O
HO

HO
OH

OH

IC50 = I.26 µM

OH

IC50 = 75.2 µM

O

O

HO

OH

OH

OH

O

COOCH 3

OH

IC50 = I.04 µM

H3 CO
RO

O

OCH 3

IC50 > 30 µM

V. Ramanandraibe et al., 10th ICSN Symposium, June 2007.
D. Rakotondramanana et al. (2007), Bioorg Med. Chem (in press).

Artemisinin derivatives
O

O

O

O

O

O
O

O

O

OH

O

O

O
O

O
OR
O

OR
RO

Herbal combination in malaria
Artemisia annua

Curcuma longa
O

O

O

O

MeO

O
O

Artemisinin

Curcumin

HO

Aphloia theiformis
OH

O

Glu

HO

OH

O

Mangiferin

OH

OH
OMe

Conclusion
Single active compound versus multi-component botanical

Biodiversity-based
approach

NCEs

Drug development

Ethnobotany-based
approach

Botanicals

IPRs
Marketing

Collaborators in the projects




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