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Combretastatin-4 (CA-4) as a tubulin polymerization inhibitor draws extensive attentions. However, due to its weak stability of <i>cis</i>-olefin and poor metabolic stability, structure modifications on <i>cis</i>-configuration are being performed. In this work, we constructed a series of novel CA-4 analogues with linkers on olefin containing diphenylethanone, <i>cis</i>-locked dihydrofuran, &#945;-substituted diphenylethanone, cyclobutane and cyclohexane on its <i>cis</i>-olefin. Cytotoxic activity of all analogues was measured by an SRB assay. Among them, compound <b>6b</b>, a by-product in the preparation of diphenylethanone analogues, was found to be the most potent cytotoxic agents against HepG2 cells with IC₅₀ values of less than 0.5 &#956;M. The two isomers of <b>6b</b> induced cellular apoptosis tested by Annexin V-FITC and propidium iodide (PI) double staining, arrested cells in the G2/M phase by PI staining analysis, and disrupted microtubule network by immunohistochemistry study in HepG2 cells. Moreover, <b>6b-(<i>E</i>)</b> displayed a dose-dependent inhibition effect for tubulin assembly in in vitro tubulin polymerization assay. In addition, molecular docking studies showed that two isomers of <b>6b</b> could bind efficiently at colchicine binding site of tubulin similar to CA-4.