Synthesis and biological evaluation of novel shikonin-benzo[b]furan derivatives as tubulin polymerization inhibitors targeting the colchicine binding site.

A novel series of shikonin-benzo[b]furan derivatives were designed and synthesized as tubulin polymerization inhibitors, and their biological activities were evaluated. Most compounds revealed the comparable anti-proliferation activities against the cancer cell lines to that of shikonin and simultaneously low cytotoxicity to non-cancer cells. Among them, compound 6c displayed powerful anti-cancer activity with the IC50 value of 0.18 µM against HT29 cells, which was significantly better than that of the reference drugs shikonin and CA-4. What's more, 6c could inhibit tubulin polymerization and compete with [3H] colchicine in binding to tubulin. Further biological studies depicted that 6c can induce cell apoptosis and cell mitochondria depolarize, regulate the expression of apoptosis related proteins in HT29 cells. Besides, 6c actuated the HT29 cell cycle arrest at G2/M phase, and influenced the expression of the cell-cycle related protein. Moreover, 6c displayed potent inhibition on cell migration and tube formation that contributes to the antiangiogenesis. These results prompt us to consider 6c as a potential tubulin polymerization inhibitor and is worthy for further study.

Design, synthesis and biological evaluation of resveratrol-cinnamoyl derivates as tubulin polymerization inhibitors targeting the colchicine binding site.

A novel series of resveratrol-cinnamoyl hybrids as tubulin polymerization inhibitors were designed and synthesized, and evaluated for their anti-proliferative activities against A549, MCF-7, HepG2, HeLa and MDA-MB-231 five cancer cell lines. Most designed compounds showed better anti-proliferative activities. Particularly, compound 6h exhibited the potent anti-proliferative activities with the IC50 value of 0.12, 0.016, 0.44, 0.37 and 0.78 µΜ against A549, MCF-7, HepG2, HeLa and MDA-231, respectively, which was superior to that of reference drug colchicine. Besides, compound 6h displayed a remarkable inhibition of tubulin polymerization and a great potency to compete with [3H] colchicine in binding to tubulin. Further studies indicated that compound 6h could induce the MCF-7 cells arrest in the G2/M phase. What' more, compound 6h induced cell apoptosis in a dose-dependent manner, and regulated the expression level of apoptosis-related proteins. These results revealed that compound 6h is a promising tubulin polymerization inhibitor for treatment of cancer and it is worthy of further exploitation.