Combretastatin-4 (CA-4) as a tubulin polymerization inhibitor draws extensive attentions. However, due to its weak stability of -olefin and poor metabolic stability, structure modifications on -configuration are being performed. In this work, we constructed a series of novel CA-4 analogues with linkers on olefin containing diphenylethanone, -locked dihydrofuran, α-substituted diphenylethanone, cyclobutane and cyclohexane on its -olefin. Cytotoxic activity of all analogues was measured by an SRB assay. Among them, compound , a by-product in the preparation of diphenylethanone analogues, was found to be the most potent cytotoxic agents against HepG2 cells with IC values of less than 0.5 μM. The two isomers of 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, 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 could bind efficiently at colchicine binding site of tubulin similar to CA-4.
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| http://dx.doi.org/10.3390/ijms21051817 | DOI Listing |
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