Conception, synthèse, caractérisation, évaluation pharmacologique et études in vivo de dérivés de l'harmine en tant que nouvelles molécules aux propriétés anticancéreuses

Promoter

Prof. Johan WOUTERS, UNamur, Laboratory of Structural Biological Chemistry (CBS)

Jury

Johan Wouters (Supervisor), Daniel Vercauteren (President), Bernard Masereel (Jury), Steve Lanners (Jury), Nicolas Willand (Jury) & Véronique Mathieu (Jury)

Summary

Harmine is a natural compound studied in the laboratory for its monoamine oxidase inhibition (MAOi). Several harmine derivatives, substituted on positions 2, 7 and/or 9, have been synthesized and studied in order to increase harmine inhibition. The natural compound is also known for its antiproliferative and anticancer effect obtained by countering the hallmarks of cancer acquired by a cancer cell. In order to develop new antiproliferative compounds, a three-step strategy has been adopted where MAOi were the research starting point.

The first part was dedicated to the development and the optimization of new harmine derivatives combining a micromolar to submicromolar antiproliferative activity and a high solubility at physiological pH. Moreover, the determination of the mechanism of action of the best candidates, trisubstituted compounds, has revealed a role of these compounds as protein synthesis inhibitors. A pharmacological study of the best antiproliferative compound, 5n, has underlined the selectivity for cancer cells compared to healthy cells and the plasmatic stability in vitro. However, the anticancer property study on a pseudometastatic murine model, after intraperitoneal injection, has highlighted the lack of 5n anticancer activity on this model. One of the given hypothesizes being the 5n poor permeability, a formulation study with complexation to cyclodextrines has been considered, in order to realize intravenous administration. This study has shown an important increased 5n solubility in presence of cyclodextrines while maintaining its submicromolar antiproliferative activity.