Antitumor agents that bind to tubulin and disrupt microtubule dynamics have attracted considerable attention in the last few years. To extend our knowledge of the thiazole ring as a suitable mimic for the cis-olefin present in combretastatin A-4, we fixed the 3,4,5-trimethoxyphenyl at the C4-position of the thiazole core. We found that the substituents at the C2- and C5-positions had a profound effect on antiproliferative activity. Comparing compounds with the same substituents at the C5-position of the thiazole ring, the moiety at the C2-position influenced antiproliferative activities, with the order of potency being NHCH(3) > Me > N(CH(3))(2). The N-methylamino substituent significantly improved antiproliferative activity on MCF-7 cells with respect to C2-amino counterparts. Increasing steric bulk at the C2-position from N-methylamino to N,N-dimethylamino caused a 1-2 log decrease in activity. The 2-N-methylamino thiazole derivatives 3b, 3d and 3e were the most active compounds as antiproliferative agents, with IC(50) values from low micromolar to single digit nanomolar, and, in addition, they are also active on multidrug-resistant cell lines over-expressing P-glycoprotein. Antiproliferative activity was probably caused by the compounds binding to the colchicines site of tubulin polymerization and disrupting microtubule dynamics. Moreover, the most active compound 3e induced apoptosis through the activation of caspase-2, -3 and -8, but 3e did not cause mitochondrial depolarization.

译文

近年来,与微管蛋白结合并破坏微管动力学的抗肿瘤剂引起了相当大的关注。为了扩展我们对噻唑环作为康美他汀A-4中顺式烯烃的合适模拟物的认识,我们将3,4,5-三甲氧基苯基固定在噻唑核心的C4位。我们发现,在C2和C5位置的取代基对抗增殖活性具有深远的影响。比较噻唑环C5位上具有相同取代基的化合物,C2位上的部分影响抗增殖活性,效力顺序为NHCH(3)> Me> N(CH(3))(2) 。相对于C 2-氨基对应物,N-甲基氨基取代基显着提高了对MCF-7细胞的抗增殖活性。从N-甲基氨基到N,N-二甲基氨基的C2位增加的空间体积导致活性降低1-2 log。 2-N-甲基氨基噻唑衍生物3b,3d和3e是最有效的化合物作为抗增殖剂,其IC(50)值从低微摩尔到一位数纳摩尔,此外,它们还对耐多药细胞具有活性系过度表达P-糖蛋白。抗增殖活性可能是由于化合物与微管蛋白聚合的秋水仙碱位点结合并破坏了微管动力学而引起的。此外,活性最高的化合物3e通过激活caspase-2,-3和-8诱导细胞凋亡,但3e不会引起线粒体去极化。

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