Abstract 2131: Synthesis and biological evaluation of novel N-alkyl derivatives of 5, 7-dibromoisatin as potent anticancer agents

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Microtubules display an important role in a variety of cellular process, including mitosis and cell division. Various anti-mitotic agents interfering with the natural dynamics of tubulin, polymerization and depolymerization inhibit cancer cell growth. The isatin is found as an endogenous molecule in humans and other mammals, and its analogues display diverse types of biological activities including anti-cancer. Recently, it has been reported that N-alkylation of 5, 7-dibromoisatin increased its cytotoxicity against a range of human cancer cell lines. In this context, it was of interest to further investigate the cytotoxicity of N-alkylated 5,7-dibromoisatin analogues like isothiocyanates and selenocyantes. Isothiocyanates are one of the most effective naturally occurring cancer chemopreventive agents that inhibit carcinogenicity in animal models. Selenium compounds have been found capable of inhibiting and/or retarding tumorigenesis in a variety of experimental animal models. Several synthetic alkyl and aryl selenocyanates have been evaluated for anticarcinogenicity in animal models. The combined literature survey of isatin derivatives, isothiocyantes and selenocyanates have prompted us to develop a novel series of 5,7-dibromoisatin containing thiocyanate, isothiocyanate and selenocyante functionalities. The cytotoxicity of a series of new N-substituted derivatives of 5,7-dibromoisatin was evaluated against a panel of four different human cancer cell lines e.g. a colon (HT29), breast (MCF-7), lung (A549) and melanoma (UACC903) and compared with the 5,7-dibromoisatin. The results showed that the cytotoxicity of the 5,7-dibromoisatin significantly increased through N-alkylation, as reported previously for the 5,7-dibromoisatin derivatives. Introduction of isothiocyante or thiocyanate groups to alkyl chain yielded the most active compounds in this series against HT29 cells. MCF-7 cell line was susceptible to compounds with substitution of selenocyanate group in the alkyl chain, indicating that selenium is playing a role in the antiproliferative activity. These selenium substituted compounds also showed good inhibitory activity against HT29 and A549 cell lines, but poor inhibitory activity in UACC903 cells. Apoptosis assay showed that at 5μM concentration, compounds containing isothiocyanates and thiocyanates induced 99% apoptosis making them the most potent compounds in HT29 cells. The selected compounds were screened for their inhibition of tubulin polymerization in a cell-free in vitro assay. The test compounds significantly inhibited the rate of microtubule polymerization at 10 μM, as compared to vinblastine, a well known microtubule destabilizer. Examination of efficacy of isothiocyanates, thiocyanates, and selenocyanates suggests that these functional groups contribute in enhancing the anticancer activity of novel isatin analogues. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2131. doi:10.1158/1538-7445.AM2011-2131