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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Synthesis and biological evaluation of novel shikonin-benzo[b]furan derivatives as tubulin polymerization inhibitors targeting the colchicine binding site
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Synthesis and biological evaluation of novel shikonin-benzo[b]furan derivatives as tubulin polymerization inhibitors targeting the colchicine binding site

机译：新型世纪素烯苯并[B]呋喃衍生物作为靶向血管素结合位点的植物聚合抑制剂的合成及生物学评价

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摘要

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 mu M 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 [H-3] 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. (C) 2020 Elsevier Masson SAS. All rights reserved.
机译：设计并合成了一种新颖的Shikonin-Benzo [B]呋喃衍生物作为管蛋白聚合抑制剂，并评估其生物活性。大多数化合物揭示了对癌细胞系的可比抗增殖活性，并同时对非癌细胞的细胞毒性低。其中，化合物6c针对HT29细胞的IC50值显示出强大的抗癌活性，IC 50值对HT29细胞显着优于Shikonin和Ca-4的参考药物。更重要的是，6C可以抑制小管蛋白聚合并与[H-3]血清晶串结合到管蛋白中。进一步的生物学研究表明，6C可以诱导细胞凋亡和细胞线粒体去极化，调节HT29细胞中凋亡相关蛋白的表达。此外，6C在G2 / M相时致动HT29细胞周期停滞，影响细胞周期相关蛋白的表达。此外，在有助于抗脑发生的细胞迁移和管形成上显示出有效的抑制。这些结果提示我们认为6C作为潜在的小管蛋白聚合抑制剂，值得进一步研究。 （c）2020 Elsevier Masson SAS。版权所有。

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