Combretastatin A-4, a potent tubulin polymn. inhibitor, caused us to synthesize a novel series of 2-amino-4-(3',4',5'-trimethoxyphenyl)-5-aryl thiazoles with the goal of evaluating the effects of substituents on the Ph at the 5-position of the thiazole skeleton on biol. activities. An ethoxy group at the para-position produced the most active compd. in the series, with IC50 values of 0.03-0.9 nM against five of seven cancer cell lines. The most active compds. retained full activity in multidrug resistant cancer cells and acted through the colchicine site of tubulin. Treated cells were arrested in the G2/M phase of the cell cycle, with cell death proceeding through an apoptotic pathway that was only partially caspase-dependent. Preliminary results suggest that, in addn. to cell death by apoptosis, cells were also killed via mitotic catastrophe as an alternative cell death mechanism.
Convergent Synthesis and Biological Evaluation of 2-Amino-4-(3',4',5'-trimethoxyphenyl)-5-aryl Thiazoles as Microtubule Targeting Agents
ROMAGNOLI, Romeo;BARALDI, Pier Giovanni;
2011
Abstract
Combretastatin A-4, a potent tubulin polymn. inhibitor, caused us to synthesize a novel series of 2-amino-4-(3',4',5'-trimethoxyphenyl)-5-aryl thiazoles with the goal of evaluating the effects of substituents on the Ph at the 5-position of the thiazole skeleton on biol. activities. An ethoxy group at the para-position produced the most active compd. in the series, with IC50 values of 0.03-0.9 nM against five of seven cancer cell lines. The most active compds. retained full activity in multidrug resistant cancer cells and acted through the colchicine site of tubulin. Treated cells were arrested in the G2/M phase of the cell cycle, with cell death proceeding through an apoptotic pathway that was only partially caspase-dependent. Preliminary results suggest that, in addn. to cell death by apoptosis, cells were also killed via mitotic catastrophe as an alternative cell death mechanism.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.