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Doctoral thesis (Dissertations and theses)
Contribution to the phytochemical study of indolomonoterpenic alkaloids isolated from Strychnos usambarensis and investigation of their activity on Plasmodium falciparum
Cao, Martine
2012
 

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Keywords :
Plasmodium falciparum ; Indolomonoterpenic alkaloids ; Strychnos usambarensis; alcaloïdes indolomonoterpéniques
Abstract :
[en] 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 (J Pharm Biomed Anal, 2011). 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 (Planta Medica, 2011). 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 (Phytochem Letters, 2012). 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 metabolomic approach displaying the metabolomic differences induced in the parasites was combined to a transcriptomic 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 in 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 transciptome 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.
Disciplines :
Pharmacy, pharmacology & toxicology
Author, co-author :
Cao, Martine ;  Université de Liège - ULiège > Département de pharmacie > Département de pharmacie
Language :
English
Title :
Contribution to the phytochemical study of indolomonoterpenic alkaloids isolated from Strychnos usambarensis and investigation of their activity on Plasmodium falciparum
Defense date :
30 May 2012
Institution :
ULiège - Université de Liège
Degree :
Doctorat en Sciences Biomédicales et Pharmaceutiques
Promotor :
Frederich, Michel  ;  Université de Liège - ULiège > Unités de recherche interfacultaires > Centre Interdisciplinaire de Recherche sur le Médicament (CIRM)
Chariot, Alain ;  Centre Hospitalier Universitaire de Liège - CHU > Service de chimie clinique
President :
Pirotte, Bernard ;  Université de Liège - ULiège > Unités de recherche interfacultaires > Centre Interdisciplinaire de Recherche sur le Médicament (CIRM)
Secretary :
Tits, Monique ;  Université de Liège - ULiège > Département de pharmacie
Jury member :
Angenot, Luc  ;  Université de Liège - ULiège > Département de pharmacie
De Mol, Patrick ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques
De Tullio, Pascal ;  Université de Liège - ULiège > Unités de recherche interfacultaires > Centre Interdisciplinaire de Recherche sur le Médicament (CIRM)
Quetin-Leclerq, Joelle
Mambu, Angèle
Funders :
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE]
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since 12 January 2015

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