Abstract
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 IC50 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.
Highlights
The natural product combretastatin A-4 (CA-4, Figure 1) was first isolated from the South African tree Combretum caffrum in 1989 [1,2] and was serendipitously discovered in 1998 by strongly blocking the polymerization of tubulin with the colchicine binding site [3]
We present the synthesis through the modification of olefin scaffold with diphenylethanone, cis-locked dihydrofuran, α-substituted diphenylethanone, cyclobutane and
We constructed a series of novel CA-4 analogues on the cis-double bond containing diphenylethanone, cis-locked dihydrofuran, α-substituted diphenylethanone, cyclobutane and cyclohexane
Summary
The natural product combretastatin A-4 (CA-4, Figure 1) was first isolated from the South African tree Combretum caffrum in 1989 [1,2] and was serendipitously discovered in 1998 by strongly blocking the polymerization of tubulin with the colchicine binding site [3]. The Z-restricted configuration can rapidly convert into 100-fold less active trans-isomerization under the conditions of suffering from heat, light and protic media [12]
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