Combretastatin-4 (CA-4) as a tubulin polymerization inhibitor draws extensive attentions. However, due to its weak stability of
cis-olefin and poor metabolic stability, structure modifications on
cis-configuration are being performed. In this work, we constructed a series of novel CA-4 analogues with
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Combretastatin-4 (CA-4) as a tubulin polymerization inhibitor draws extensive attentions. However, due to its weak stability of
cis-olefin and poor metabolic stability, structure modifications on
cis-configuration are being performed. In this work, we constructed a series of novel CA-4 analogues with linkers on olefin containing diphenylethanone,
cis-locked dihydrofuran, α-substituted diphenylethanone, cyclobutane and cyclohexane on its
cis-olefin. Cytotoxic activity of all analogues was measured by an SRB assay. Among them, compound
6b, a by-product in the preparation of diphenylethanone analogues, was found to be the most potent cytotoxic agents against HepG2 cells with IC
50 values of less than 0.5 μM. The two isomers of
6b 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,
6b-(E) 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
6b could bind efficiently at colchicine binding site of tubulin similar to CA-4.
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