Design and synthesis of bis(indolyl)ketohydrazide-hydrazones: Identification of potent and selective novel tubulin inhibitors

Abstract

A novel series of ketohydrazide-hydrazones as analogues of naturally occurring coscinamides has been synthesized and evaluated for their anticancer activity against five cancer cell lines. Of the twenty-synthesized ketohydrazide-hydrazones, compounds, 21c, 21f, 21g, 21k and 21o showed cytotoxic effects (less than 50% cell survival) against multiple cancer cell lines when tested at a final concentration of 10 μM. IC₅₀ of three compounds 21f, 21k and 21o was determined to be less than 5 μM for all tested cancer cell lines. Compound 21k exhibited significant anticancer activity against MCF-7, MDA-MB-231, HCT-116 and JURKAT cancer cell lines with IC₅₀ values of 0.8 μM, 0.50 μM, 0.15 μM, and 0.22 μM, respectively. Also, 21k was found to be more selectively cytotoxic against tumor cells when compared to normal cells. Preliminary mechanism of action studies indicated that the most active compound 21k induced caspase-dependent apoptosis in cells. 21k arrests cell cycle in G2/M phase by inhibiting of tubulin polymerization (IC₅₀ = 0.6 μM).

Keywords: Apoptosis; Bisindoles; Coscinamides; Cytotoxicity; Ketohydrazide-hydrazones; Tubulin inhibitor.