Synthèse de nouveaux phosphinosucres et pseudo-disaccharides à activité anticancéreuse

Abstract

The Phostines represent a new class of glycomimetics, containing a phosphinolactone function instead of the anomeric carbon. Their synthesis was achieved by the reaction of protected furanose with various H-phosphinates, in the presence of a base. These compounds have been found to be very effective in vitro and in vivo against rat and human glioblastoma cells. In this project, our first goal was to obtain the most active phostine with higher diastereoselectivity. Different reactions were tested, changing the base or its counter ion. A very slight improvement was noted with cesium methoxide, favoring the glucose-like derivative. In the context of improving the anticancer activity and to study the biodistribution of the phostines, different chemical modifications were carried out. Dihydroxy-2,3- and 2,6- oxaphosphinanes, thiophostines and phostines of the L series were synthesized. Therefore, variations in α position of the phosphorus atom have produced halogenated phostines and two new products: furanosylphosphinic acid and the oxaphosphine-3-ene.The chemical reactivity of the enol ether of this latter has been examined by synthesizing β-ketophosphinate and β-enaminophosphinates. Finally, pseudo-disaccharides were synthesized to improve the bioavailability of phostines. The tested phostines have exhibited anticancer properties at nanomolar concentration against different cell lines, showing the ability of this family of compounds to fight some types of cancers.