Synthesis and biological evaluation of diarylthiazole derivatives as antimitotic and antivascular agents with potent antitumor activity
Synthesis and biological evaluation of diarylthiazole derivatives as antimitotic and antivascular agents with potent antitumor activity
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具有有效抗肿瘤活性的抗有丝分裂和抗血管药物二芳基噻唑衍生物的合成和生物学评价
DOI：
10.1016/j.bmc.2015.04.055
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发表时间：
2015
影响因子：
3.5
通讯作者：
Chen Lijuan
中科院分区：
文献类型：
--
作者：
Wang Fang;Yang Zhuang;Liu Yibin;Ma Liang;Wu Yuzhe;He Lin;Shao Mingfeng;Yu Kun;Wu Wenshuang;Pu Yuzhi;Nie Chunlai;Chen Lijuan
在Combrestatatin A-4（CA-4）的化学修饰基础上，通过改变噻唑环上N、S原子的位置，合成了一系列4，5-二芳基噻唑衍生物。它们的抗增殖活性进行了评估，并确定为新的微管去稳定剂。构效关系研究表明，2-氨基取代噻唑的C-4位为3，4，5-三甲氧基苯基，C-5位为4-乙氧基苯基的化合物8a具有最强的抑制活性，对5种人癌细胞的IC 50值为8.4-26.4 nM，与CA-4相当。此外，8显示出作为微管蛋白聚合抑制剂的效力，具有秋水仙碱位点结合能力和对P-糖蛋白过表达的多药耐药细胞系的生长的相当程度的抑制。作用机制研究表明，8-aca可使肿瘤细胞阻滞于G2/M期，导致细胞凋亡。作为一种新的微管蛋白去稳定剂，8a也被发现具有高的抗血管活性，因为它浓度依赖性地减少细胞迁移和破坏HUVEC细胞的毛细血管样管形成。8a对HCT 116和SK-OV-3移植瘤的生长抑制率分别为55.12%和72.7%。我们的研究表明，8a是一种很有前途的微管靶向抗肿瘤药物。
By switching position of the N and S atom in the thiazole ring which were similar to the previously reported agent 5-(4-ethoxyphenyl)-4-(3′,4′,5′-trimethoxyphenyl)thiazol-2-amine, a series of 4,5-diarylthiazole derivatives were synthesized using Friedel–Crafts reaction based on chemical modification of Combrestatatin A-4 (CA-4). Their antiproliferative activities were evaluated and identified as new microtubule destabilizing agents. Structure–activity relationship study indicated that compound8awith 3,4,5-trimethoxyphenyl group at the C-4 position and 4-ethoxyphenyl group at the C-5 position of 2-amino substituted thiazole was of the most potent inhibitory activity in this series.8awas found to exhibit the IC50values of 8.4–26.4 nM in five human cancer cell lines, with comparable inhibition effects toCA-4. Moreover,8ashowed potency as a tubulin polymerization inhibitor, with colchicine site binding ability and comparable extent of inhibition against the growth of P-glycoprotein over-expressing multidrug resistant cell lines. Mechanism studies revealed that8acould block the progression of cell cycle in the G2/M phase and result in cellular apoptosis in cancer cells. As a new tubulin destabilizing agent,8awas also found high antivascular activity as it concentration-dependently reduced the cell migration and disrupted capillary like tube formation of HUVEC cells. Furthermore,8asignificantly suppressed the tumor growth in HCT116 and SK-OV-3 xenograft models with tumor growth inhibitory rate of 55.12% and 72.7%, respectively. Our studies highlighted that8awas a promising microtubule targeting antitumor agent.