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Page de résumé pour ULgetd-05142012-160624

Auteur : Cao, Martine
E-mail de l'auteur : Martine.Cao@ulg.ac.be
URN : ULgetd-05142012-160624
Langue : Anglais/English
Titre : Contribution to the phytochemical study of indolomonoterpenic alkaloids isolated from Strychnos usambarensis and investigation of their activity on Plasmodium falciparum
Intitulé du diplôme : Doctorat en sciences biomédicales et pharmaceutiques
Département : Médecine - Département de pharmacie
Jury :
Nom : Titre :
ANGENOT, Luc Membre du jury/Committee Member
CHARIOT, Alain Membre du jury/Committee Member
DE MOL, Patrick Membre du jury/Committee Member
DE TULLIO, Pascal Membre du jury/Committee Member
MAMBU, Angèle Membre du jury/Committee Member
QUETIN-LECLERCQ, Joëlle Membre du jury/Committee Member
TITS, Monique Membre du jury/Committee Member
PIROTTE, Bernard Président du jury/Committee Chair
FREDERICH, Michel Promoteur/Director
Mots-clés :
  • Plasmodium falciparum
  • Indolomonoterpenic alkaloids/alcaloïdes indolomonoterpéniques
  • Strychnos usambarensis
Date de soutenance : 2012-05-30
Type d'accès : Restreint/Intranet
Résumé :

Our research focuses on the extended study of antimalarial and anticancer alkaloids isolated from Strychnos usambarensis (leaves and fruits), and is subdivided into two main axes:

- The development of a purification method for natural compounds such as tertiary indolomonoterpenic alkaloids (in particular for isostrychnopentamine or ISP) to improve the isolation process and to get significant quantities of purified compounds.

- The investigation of the pharmacological properties of ISP, especially on Plasmodium falciparum.

The first part of the thesis is devoted to the phytochemical study of S. usambarensis leaves. It includes the development and the optimization of a simple and rapid HPLC method in order to perform a one-step transposition in preparative scale.

In parallel to this work, a brand new alkaloid was isolated from the crude alkaloid extract of S. usambarensis leaves, 17-O-acetyl, 10-hydroxycorynantheol. The compound, assessed for its antiplasmodial activity on the 3D7 and W2 strains of P. falciparum, represents one of the most active monoindolic alkaloid known to date with a remarkable selectivity for the parasite.

Fruits were also investigated in order to identify the main components and maybe the presence of ISP. Two major alkaloids were characterized by analytical HPLC and were therefore studied in LC-NMR and mass spectrometry (MS) after solid phase extraction (SPE): palicoside and akagerine.

In addition, we also carried out hemisynthesis of isostrychnopentamine during the PhD mandate. The concept was to hemisynthetize ISP from 11-OH usambarine, a tertiary alkaloid more abundant in the leaves. Unfortunately, the first experiments were not as conclusive as expected.

The second part of the thesis concerns the investigation of the mode of action of ISP on P. falciparum. A metabolomics approach displaying the metabolomic differences induced in the parasites was combined to a transcriptomics study evaluating genes expression via a microarray analysis, in order to better understand the biological processes involved in P. falciparum in response to ISP.

For this purpose we performed a study using 1H NMR metabolomics on culture media of P. falciparum under ISP treatment. In addition, we investigated gene activation using microarrays and analyzed the alterations of the P. falciparum 3D7 transcriptome in synchronous cultures after exposure to ISP. Differences in gene expression were highlighted: out of the 4700 genes analyzed, 84 were differentially expressed, 40 over-expressed and 44 under-expressed and some of them were related to specific metabolic pathways.

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