Dipartimento di Scienze Farmaceutiche, Università di Ferrara, 44100 Ferrara, Italy.
Bioorg Med Chem Lett. 2011 May 1;21(9):2746-51. doi: 10.1016/j.bmcl.2010.11.083. Epub 2010 Nov 21.
Microtubules are dynamic structures that play a crucial role in cellular division and are recognized as an important target for cancer therapy. In search of new compounds with strong antiproliferative activity and simple molecular structure, a new series of 2-amino-3-(3',4',5'-trimethoxybenzoyl)-5-(hetero)aryl ethynyl thiophene derivatives was prepared by the Sonogashira coupling reaction of the corresponding 5-bromothiophenes with several (hetero)aryl acetylenes. When these compounds were analyzed in vitro for their inhibition of cell proliferation, the 2- and 3-thiophenyl acetylene derivatives were the most powerful compounds, both of which exerted cytostatic effects at submicromolar concentrations. In contrast, the presence of a more flexible ethyl chain between the (hetero)aryl and the 5-position of the thiophene ring resulted in significant reduction in activity relative to the 5-(hetero)aryl acetylene substituted derivatives. The effects of a selected series of compounds on cell cycle progression correlated well with their strong antiproliferative activity and inhibition of tubulin polymerization. We found that the antiproliferative effects of the most active compounds were associated with increase of the proportion of cells in the G(2)/M and sub-G(1) phases of the cell cycle.
微管是一种动态结构，在细胞分裂中起着至关重要的作用，被认为是癌症治疗的一个重要靶点。为了寻找具有强增殖抑制活性和简单分子结构的新型化合物，我们通过 Sonogashira 偶联反应，将相应的 5-溴噻吩与几种（杂）芳基乙炔反应，合成了一系列新的 2-氨基-3-（3'，4'，5'-三甲氧基苯甲酰基）-5-（杂）芳基乙炔基噻吩衍生物。当这些化合物在体外分析其对细胞增殖的抑制作用时，2-和 3-噻吩基乙炔基衍生物是最有效的化合物，它们都在亚微摩尔浓度下发挥细胞生长抑制作用。相比之下，（杂）芳基与噻吩环 5 位之间存在更灵活的乙基链，导致其活性相对于 5-（杂）芳基乙炔取代衍生物显著降低。所选化合物系列对细胞周期进程的影响与它们强烈的增殖抑制活性和微管聚合抑制作用密切相关。我们发现，最活跃的化合物的增殖抑制作用与细胞周期中 G(2)/M 和 sub-G(1)期细胞比例的增加有关。
