Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Ferrara, Italy.
J Med Chem. 2010 May 27;53(10):4248-58. doi: 10.1021/jm100245q.
A series of 1-aryl-5-(3',4',5'-trimethoxyphenyl) derivatives and their related 1-(3',4',5'-trimethoxyphenyl)-5-aryl-1,2,4-triazoles, designed as cis-restricted combretastatin analogues, were synthesized and evaluated for antiproliferative activity, inhibitory effects on tubulin polymerization, cell cycle effects, and apoptosis induction. Their activity was greater than, or comparable with, that of the reference compound CA-4. Flow cytometry studies showed that HeLa and Jurkat cells treated with the most active compounds 4l and 4o were arrested in the G2/M phase of the cell cycle in a concentration dependent manner. This effect was accompanied by apoptosis of the cells, mitochondrial depolarization, generation of reactive oxygen species, activation of caspase-3, and PARP cleavage. Compound 4l was also shown to have potential antivascular activity, since it induced endothelial cell shape change in vitro and disrupted the sprouting of endothelial cells in the chick aortic ring assay.
一系列 1-芳基-5-(3',4',5'-三甲氧基苯基)衍生物及其相关的 1-(3',4',5'-三甲氧基苯基)-5-芳基-1,2,4-三唑，被设计为顺式限制型康普瑞汀类似物，被合成并评估了其抗增殖活性、对微管聚合的抑制作用、细胞周期效应和细胞凋亡诱导作用。它们的活性大于或与参考化合物 CA-4 相当。流式细胞术研究表明，用最活性化合物 4l 和 4o 处理的 HeLa 和 Jurkat 细胞在细胞周期的 G2/M 期被浓度依赖性地阻滞。这种作用伴随着细胞凋亡、线粒体去极化、活性氧的产生、caspase-3 的激活和 PARP 切割。化合物 4l 还显示出潜在的抗血管生成活性，因为它在体外诱导内皮细胞形态改变，并破坏鸡主动脉环试验中内皮细胞的发芽。
