Synthesis and evaluation of a series of resveratrol analogues as potent anti-cancer agents that target tubulin

Abstract

A series of novel diarylacrylonitrile and <i>trans</i>-stilbene analogues of resveratrol has been synthesized and evaluated for their anticancer activities against a panel of 60 human cancer cell lines. The diarylacrylonitrile analogues <b>3b</b> and <b>4a</b> exhibited the most potent anticancer activity of all the analogues synthesized in this study, with GI₅₀ values of < 10 nM against almost all the cell lines in the human cancer cell panel. Compounds <b>3b</b> and <b>4a</b> were also screened against the acute myeloid leukemia (AML) cell line, MV4-11, and were found to have potent cytotoxic properties that are likely mediated through inhibition of tubulin polymerization. Results from molecular docking studies indicate a common binding site for <b>4a</b> and <b>3b</b> on the 3,3-tubulin heterodimer, with a slightly more favorable binding for <b>3b</b> compared to <b>4a</b>; this is consistent with the results from the microtubule assays, which demonstrate that <b>4a</b> is more potent than <b>3b</b> in inhibiting tubulin polymerization in MV4-11 cells. Taken together, these data suggest that diarylacrylonitriles <b>3b</b> and <b>4a</b> may have potential as antitubulin therapeutics for treatment of both solid and hematological tumors.