Design, synthesis and biological evaluation of new carbazole derivatives as anti-cancer and anti-migratory agents.

Based on the efficacy of EHop-016 as an inhibitor of migration and Rac1 activation, a new series of carbazole derivatives has been synthesized. Cytotoxic and anti-migratory effects of these compounds were evaluated in MCF-7 and MDA-MB-231 breast cancer cell lines. Preliminary investigations of their anticancer activity demonstrated that several compounds have moderate antiproliferative effects on cancer cell lines with GI50 values in the range of 13-50 µM. Furthermore, compounds 3b and 11b inhibit migration activity of metastatic cell line MDA-MB-231 by 32% and 34%, respectively. Compound 11b was shown to inhibit activation of the Rho GTPase Rac1 by 55% at 250 nM in both MDA-MB-231 and MDA-MB-435 cell lines. Compared with the IC50 of Rac1 inhibition by lead compound EHop-016 of 1.1 µM, compound 11b demonstrates 4X improved in vitro efficacy.