Design, synthesis and biological evaluation of resveratrol-cinnamoyl derivates as tubulin polymerization inhibitors targeting the colchicine binding site
Design, synthesis and biological evaluation of resveratrol-cinnamoyl derivates as tubulin polymerization inhibitors targeting the colchicine binding site
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作为针对秋水仙碱结合位点的微管蛋白聚合抑制剂的白藜芦醇-肉桂酰衍生物的设计、合成和生物学评价
DOI：
10.1016/j.bioorg.2019.103319
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发表时间：
2019
影响因子：
5.1
通讯作者：
Kong Ling-Yi
中科院分区：
文献类型：
--
作者：
Yin Yong;Lian Bao-Ping;Xia Yuan-Zheng;Shao Yu-Ying;Kong Ling-Yi
设计并合成了一系列新型微管蛋白聚合抑制剂白藜芦醇-肉桂酰基杂合物，并对A549、MCF-7、HepG 2、HeLa和MDA-MB-231五种肿瘤细胞株进行了体外抗增殖活性评价。大多数设计的化合物显示出较好的抗增殖活性。其中化合物6 hex对A549、MCF-7、HepG 2、HeLa和MDA-231的IC 50值分别为0.12、0.016、0.44、0.37和0.78 μ M，其抑制增殖活性上级优于对照药物秋水仙碱。此外，化合物6 h对微管蛋白聚合有明显的抑制作用，并能与[3 H]秋水仙碱竞争结合微管蛋白。进一步的研究表明化合物6 h可诱导MCF-7细胞阻滞于G2/M期。化合物6 h呈剂量依赖性诱导细胞凋亡，并调节凋亡相关蛋白的表达水平。这些结果表明化合物6是一种很有前途的微管蛋白聚合抑制剂，具有进一步开发的价值。
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, compound6hexhibited the potent anti-proliferative activities with the IC50value 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, compound6hdisplayed a remarkable inhibition of tubulin polymerization and a great potency to compete with [3H] colchicine in binding to tubulin. Further studies indicated that compound6hcould induce the MCF-7 cells arrest in the G2/M phase. What’ more, compound6hinduced cell apoptosis in a dose-dependent manner, and regulated the expression level of apoptosis-related proteins. These results revealed that compound6his a promising tubulin polymerization inhibitor for treatment of cancer and it is worthy of further exploitation.