5,5′-Substituted Indirubin-3′-oxime Derivatives as Potent Cyclin-Dependent Kinase Inhibitors with Anticancer Activity

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• 作者：Soo-Jeong Choi ; Jung-Eun Lee ; Soon-Young Jeong ; Isak Im ; So-Deok Lee ; Eun-Jin Lee ; Sang Kook Lee ; Seong-Min Kwon ; Sang-Gun Ahn ; Jung-Hoon Yoon ; Sun-Young Han ; Jae-Il Kim ; Yong-Chul Kim
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：May 13, 2010
• 年：2010
• 卷：53
• 期：9
• 页码：3696-3706
• 全文大小：1020K
• 年卷期：v.53,no.9(May 13, 2010)
• ISSN：1520-4804

文摘

To enhance the ability of indirubin derivatives to inhibit CDK2/cyclin E, a target of anticancer agents, we designed and synthesized a new series of indirubin-3′-oxime derivatives with combined substitutions at the 5 and 5′ positions. A molecular docking study predicted the binding of derivatives with OH or halogen substitutions at the 5′ position to the ATP binding site of CDK2, revealing the critical interactions that may explain the improved CDK2 inhibitory activity of these derivatives. Among the synthesized derivatives, the 5-nitro-5′-hydroxy analogue 3a and the 5-nitro-5′-fluoro analogue 5a displayed potent inhibitory activity against CDK2, with IC₅₀ values of 1.9 and 1.7 nM, respectively. These derivatives also showed antiproliferative activity against several human cancer cell lines, with IC₅₀ values of 0.2−3.3 μM. A representative analogue, 3a, showed greater than 500-fold selectivity for CDK relative to selected kinase panel and potent in vivo anticancer activity.