Ricerc@Sapienza

Arylthioindoles (ATIs) and aroylindoles (AIs) are two classes of modern and potent colchicine-binding site inhibitors of tubulin polymerization and cancer cell growth, recently developed by our research group. Unpublished structure-activity relationship studies pointed out that the introduction of a triazole ring at position 6 or 7 of the indole nucleus improved both water solubility and anticancer activity. Based upon these promising results, aim of this research project is a hit lo lead optimization process by introducing different basic groups (e.g., methylamino, dimethylamino, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl and morpholino) at position 6 or 7 of the indole nucleus. In addition, the bioisosteric substitution of the sulphur atom with a ketone bridge and the introduction of a phenyl group at position 2 of the indole nucleus will be explored in all the new derivatives.
Molecular modelling studies will be carried out to clarify the binding mode of the new derivatives into the colchicine-binding site of tubulin, and according to the obtained results the most promising compounds will be prepared. The use of both microwave-assisted synthesis and fully automated flash chromatography system will allow us to slash both reaction and purification times. All the newly synthesized compounds, prepared as free bases and ionic salts, will be tested for determining their ability to inhibit tubulin assembly, binding of colchicine to tubulin as well as MCF-7 human breast carcinoma cell growth. Then, the most active compounds will be evaluated using different cancer cell lines and fully characterized in terms of effects on cell cycle progression, inhibition of microtubule assembly and induction of mitotic arrest or death, as well as pharmacokinetic profile.