Imidazolone–amide bridges and their effects on tubulin polymerization in cis-locked vinylogous combretastatin-A4 analogues: Synthesis and biological evaluation

A series of novel combretastatin-A4 analogues in which the cis-olefinic bridge is replaced by an imidazolone–amide were synthesized, and their cytotoxicity and tubulin-polymerization inhibitory activities were evaluated. These compounds appear to be potential tubulin-polymerization inhibitors. Compounds 10, 9b and 9c, bearing 3′-NH2-4′-OCH3, 4′-CH3 and 3′-CH3-substituted 1-phenyl B-ring, confer optimal bioactivity. The binding modes of these compounds to tubulin were obtained by molecular docking, which can explain the compounds’ structure–activity relationship. The studies presented here provide a new structural type for the development of novel antitumor agents.

Several CA-4 analogues bearing an imidazolone–amide moiety showed cytotoxicity and tubulin polymerization inhibitory activity. The binding mode of compound 10 with optimal bioactivity to tubulin was obtained by molecular docking.Figure optionsDownload as PowerPoint slide