Design, synthesis, and biological evaluation of hydantoin bridged analogues of combretastatin A-4 as potential anticancer agents.

A series of novel hydantoin-bridged analogues of combretastatin A-4 (CA-4) were designed, synthesized and evaluated for antiproliferative activities in vitro and in vivo. The most potent compound 8d, showed potent cytotoxicity against four human cancer cell lines with IC ₅₀ values of 0.186-0.279 μM, and possessed the efficacy of inhibiting tubulin polymerization, disrupting in vitro vascularization, blocking cell cycle in G ₂ /M phase and inducing cell apoptosis. In the nude mice xenograft model, 8d significantly inhibited the tumor growth and showed low toxicity. Further chiral separation proved (R)-(-)-8d to be the preferential enantiomer with IC ₅₀ values of 0.081-0.157 M. These results indicated that the hydantoin derivatives merit further investigation as potential anticancer agents that inhibit tubulin polymerization.
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