Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
Bioorg Med Chem. 2010 Oct 1;18(19):7092-100. doi: 10.1016/j.bmc.2010.07.072. Epub 2010 Aug 6.
Microtubule cytoskeletons are involved in many essential functions throughout the life cycle of cells, including transport of materials into cells, cell movement, and proper progression of cell division. Small compounds that can bind at the colchicine site of tubulin have drawn great attention because these agents can suppress or inhibit microtubule dynamics and tubulin polymerization. To find novel tubulin polymerization inhibitors as anti-mitotic agents, we performed a virtual screening study of the colchicine binding site on tubulin. Novel tubulin inhibitors were identified and characterized by their inhibitory activities on tubulin polymerization in vitro. The structural basis for the interaction of novel inhibitors with tubulin was investigated by molecular modeling, and we have proposed binding models for these hit compounds with tubulin. The proposed docking models were very similar to the binding pattern of colchicine or podophyllotoxin with tubulin. These new hit compound derivatives exerted growth inhibitory effects on the HL60 cell lines tested and exhibited strong cell cycle arrest at G2/M phase. Furthermore, these compounds induced apoptosis after cell cycle arrest. In this study, we show that the validated derivatives of compound 11 could serve as potent lead compounds for designing novel anti-cancer agents that target microtubules.
微管细胞骨架参与细胞生命周期中的许多基本功能，包括物质向细胞内的运输、细胞运动和细胞分裂的正常进行。能够结合微管蛋白秋水仙碱结合部位的小分子化合物引起了极大的关注，因为这些试剂可以抑制或抑制微管动力学和微管蛋白聚合。为了寻找新型的微管蛋白聚合抑制剂作为抗有丝分裂剂，我们对微管蛋白上的秋水仙碱结合位点进行了虚拟筛选研究。通过体外微管蛋白聚合抑制活性对新型微管抑制剂进行了鉴定和表征。通过分子建模研究了新型抑制剂与微管相互作用的结构基础，并提出了这些命中化合物与微管相互作用的结合模型。提出的对接模型与秋水仙碱或鬼臼毒素与微管的结合模式非常相似。这些新的命中化合物衍生物对测试的 HL60 细胞系表现出生长抑制作用，并在 G2/M 期表现出强烈的细胞周期停滞。此外，这些化合物在细胞周期停滞后诱导细胞凋亡。在这项研究中，我们表明化合物 11 的验证衍生物可以作为设计靶向微管的新型抗癌药物的有效先导化合物。
