Synthesis and biological evaluation of a novel class of isatin analogs as dual inhibitors of tubulin polymerization and Akt pathway

摘要

A novel series of 5,7-dibromoisatin analogs were synthesized and evaluated for their cytotoxicities against four human cancer cell lines including colon HT29, breast MCF-7, lung A549 and melanoma UACC903. Analogs >6, >11 and >13 displayed good in vitro anticancer activity on the HT29 human colon cancer cell line in the 1 µM range. Analogs >5, >9 and >12, containing a selenocyanate group in the alkyl chain were the most promising compounds on the breast cancer MCF-7 cell line. Biological assays relating to apoptosis were performed to understand the mechanism of action of these analogs. Compounds >5 and >6 were found to inhibit tubulin polymerization to the same extent as the anticancer drug vinblastine sulfate, but compounds >11 and >13 inhibited significantly better than vinblastine. Further western blot analysis suggested that compound >6 at 2 µM reduced both levels and phosphorylation state of Akt. Compounds >11 and >13 at 1 µM caused reduced Akt protein levels and strongly suppressed the phosphorylation of Akt. Therefore, >11 and >13 were demonstrated as efficient dual inhibitors of both tubulin polymerization and the Akt pathway and good candidates for further study. More importantly, the strategy of microtubule and Akt dual inhibitors might be a promising direction for developing novel drugs for cancer.