New antitubulin derivatives in the combretastatin A4 series: synthesis and biological evaluation

Two series of combretastatin A4 derivatives (acrylamide = carboxamide and carbamate) were synthesized in order to improve the water solubility and stabilize the cis-configuration of the double bond. Their cytotoxic effects were evaluated against MCF-7, KB-3-1 and IGROV human cancer cell lines, as well as their inhibitory activity on tubulin polymerization. Results were compared to those of carboxamide 1, chosen as reference. Potent inhibitions were observed on both tests in the carboxamide series, particularly for compound 4d bearing a fluorine group in replacement of the 3-hydroxyl of CA4. In contrast, most of the carbamates were either inactive or displayed only moderate cytotoxicities. Interestingly, a submicromolar IC50 was measured on MCF-7 cells for 6g, although this compound was totally devoid of antitubulin activity.

A series of carboxamide and carbamate analogues of combretastatin A4 were synthesized and evaluated. Several compounds exhibited strong cytotoxicities correlated with a potent inhibition of tubulin assembling.Figure optionsDownload as PowerPoint slide