Dioxol and dihydrodioxin analogs of 2- and 3-phenylacetonitriles as potent anti-cancer agents with nanomolar activity against a variety of human cancer cells

摘要

A small library of (Z)-2-(benzo[d][1,3]dioxol-5-yl) and (Z)-2,3-dihydrobenzo [b][1,4] dioxin-6-yl analogs of 2- and 3-phenylacetonitriles has been synthesized and evaluated for their anti-cancer activities against a panel of 60 human cancer cell lines. The dihydrodioxin analog >3j and dioxol analogs >5e and >7e exhibited the most potent anti-cancer activity of all the analogs synthesized in this study, with GI50 values of <100 nM against almost all of the cell lines in the human cancer cell panel. Of these three, only compound >3j inhibited tubulin polymerization to any degree in vitro. The binding modes of >3j and the structurally related tubulin-inhibitor >DMU-212 were determined by virtual docking studies with tubulin dimer. Compound >3j docked at the colchicine-binding site at the dimer interface of tubulin. The Full-Fitness (FF) score of >3j was observed to be substantially higher than >DMU-212, which agrees well with the observed anti-cancer potency (GI50 values). The mechanism by which dioxol analogs >5e and >7e exert their cytotoxic effects remains unknown at this stage, but it is unlikely that they affect tubulin dynamics. Nevertheless, these findings suggest that both dioxol and dihydrodioxin analogs of phenylacrylonitrile may have potential for development as clinical candidates to treat a variety of human cancers.