State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, People's Republic of China.
J Med Chem. 2013 Feb 28;56(4):1467-77. doi: 10.1021/jm3014663. Epub 2013 Feb 12.
Several new series of 5,6,7-trimethoxyindole derivatives were synthesized and their structure-activity relationships (SARs) were studied. Some of these compounds exhibited strong antiproliferative activities in the submicromolar range. N-Methyl-5,6,7-trimethoxylindoles 21 and 31 displayed the highest antiproliferative activities, with IC50 values ranging from 22 to 125 nM in four human cancer cell lines and activated human umbilical vein endothelial cells (HUVECs). In addition to vascular disrupting activity verified by in vitro assays, compounds 21 and 31 displayed much higher selectivity for activated HUVECs versus quiescent HUVECs than those of colchicine and combretastatinA-4. The polymerization of cancer cell tubulin was inhibited and the cell cycle was arrested in the G2/M phase after treatment with 21 and 31. It was showed that 21 disrupted tumor vasculature by use of in vivo assay. Our results suggest that these two new compounds we synthesized may become the promising leads for the development of vascular disrupting agents.
我们合成了几类新的 5,6,7-三甲氧基吲哚衍生物，并研究了它们的构效关系（SARs）。其中一些化合物在亚微摩尔范围内表现出很强的抗增殖活性。N-甲基-5,6,7-三甲氧基吲哚 21 和 31 表现出最高的抗增殖活性，在四种人癌细胞系和激活的人脐静脉内皮细胞（HUVECs）中，IC50 值范围为 22 至 125 nM。除了通过体外测定验证的血管破坏活性外，化合物 21 和 31 对激活的 HUVECs 的选择性比秋水仙碱和 combretastatin A-4 对静止的 HUVECs 高得多。用 21 和 31 处理后，癌细胞微管蛋白的聚合被抑制，细胞周期被阻滞在 G2/M 期。结果表明，21 可通过体内试验破坏肿瘤血管。我们的研究结果表明，这两种新化合物可能成为开发血管破坏剂的有前途的先导化合物。
