School of Pharmacy, College of Pharmacy, Taipei Medical University, No 250, Wuxing Street, Taipei 11031, Taiwan, ROC.
Eur J Med Chem. 2011 Sep;46(9):3623-9. doi: 10.1016/j.ejmech.2011.04.065. Epub 2011 May 20.
A novel series of the biheterocycles-based compounds with core structure distinguished from combretastatin A-4 (1) and colchicine (5) have been synthesized and evaluated as potent anti-mitotic agents. Compound 1-(4'-Indolyl and 6'-quinolinyl)-4,5,6-trimethoxyindoles 13 and 19 showed substantial anti-proliferative activity against various human cancer cell lines, regardless to the tissue origin and the expression of multiple-drug resistance MDR1, with a mean IC(50) value of 38 and 24 nM respectively. Compound 13 (IC(50) = 1.7 μM) also exhibited similar anti-tubulin activities to 1 (IC(50) = 1.8 μM) and displayed strong binding property to the colchicine binding site on the microtubules. Computational modeling analysis revealed that the binding mechanism of compound 13 is similar to that of CA4.
一种新型的双杂环类化合物系列，其核心结构不同于 combretastatin A-4（1）和秋水仙碱（5），已被合成并评估为有效的有丝分裂抑制剂。化合物 1-(4'-吲哚基和 6'-喹啉基)-4,5,6-三甲氧基吲哚 13 和 19 对各种人类癌细胞系表现出显著的抗增殖活性，与组织来源和多药耐药 MDR1 的表达无关，平均 IC（50）值分别为 38 和 24 nM。化合物 13（IC（50）= 1.7 μM）也表现出与 1（IC（50）= 1.8 μM）相似的抗微管蛋白活性，并显示出与微管上秋水仙碱结合位点的强结合特性。计算建模分析表明，化合物 13 的结合机制类似于 CA4。
