Thèse de doctorat en Chimie médicinale et pharmaceutique
Sous la direction de Christian Cavé.
Soutenue en 2009
à Paris 11 .
Betulinic acid is a natural compound presenting interesting anti-VIH and anti-tumoral activities but with an unsufficient solubility and bioavailability. So numerous structure-activity relationship studies show that C3, C20 and C28 pharmacomodulations on betulinic acid provided derivatives with not only improved antitumoral and anti-VIH activities but also with higher solubility compared to the relative molecule. In this thesis, we proposed the synthesis of new betulinic acid derivatives exhibiting a of diacid or diester side chain linked in C28 via an amide or ester group, to increase anticancerous and anti-VIH activities as well as hydrosolubility. Considering that the chemical function in position C28 of betulinic acid is an acidic function, we thought to link to this function chiral b-hydroxy and b-aminoesters, resulting from diastereoselective reductions of b-keto and b-iminoesters obtained by asymmetric Michael reaction. Our project is divided into three parts: synthesis of Michael adducts, diastereoselective reduction of the previously obtained b-keto and b-iminoester adducts, and finally their fixation in C28 on the betulinic acid after protection of the alcohol in C3 and activation of the carboxylic acid function. Several trials were performed to couple b-hydroxy and b-aminoesters with betulinic acid in C28 either in solution, or on solid support.