Design and Biological Evaluation of Novel Tubulin Inhibitors as Antimitotic Agents Using a Pharmacophore Binding Model with Tubulin

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• 作者：Do Yoon Kim ; Kyun-Hwan Kim ; Nam Doo Kim ; Ki Young Lee ; Cheol Kyu Han ; Jeong Hyeok Yoon ; Seung Kee Moon ; Sung Sook Lee ; Baik L. Seong
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：September 21, 2006
• 年：2006
• 卷：49
• 期：19
• 页码：5664 - 5670
• 全文大小：777K
• 年卷期：v.49,no.19(September 21, 2006)
• ISSN：1520-4804

文摘

Although the structure has been elucidated for the binding of colchicine and podophyllotoxin as potentdestabilizer for microtubule formation, very little is known about MDL-27048, a competitive inhibitor forcolchicine and podophyllotoxin. The structural basis for the interaction of antimitotic agents with tubulinwas investigated by molecular modeling, and we propose binding models for MDL-27048 against tubulin.The proposed model was not only consistent with previous competition experiment data between colchicineand MDL-27048, but further suggested an additional binding cavity on tubulin. Based on this finding fromthe proposed MDL-tubulin complex, we performed molecular design studies to identify new antimitoticagents. These new chalcone derivatives exerted growth inhibitory effects on all four human hepatoma andone renal epithelial cell lines tested and induced strong cell cycle arrest at G2/M phase. Furthermore, thesecompounds exhibited a strong inhibitory effect on tubulin polymerization in vitro. Therefore, we suggestthat the validated MDL-27048 model would serve as a potent platform for designing new molecular entitiesfor anticancer agents targeted to microtubules.