Structure-Based Design, Synthesis, and Biological Evaluation of Potent and Selective Macrocyclic Checkpoint Kinase 1 Inhibitors

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• 作者：Zhi-Fu Tao ; Le Wang ; Kent D. Stewart ; Zehan Chen ; Wendy Gu ; Mai-Ha Bui ; Philip Merta ; Haiying Zhang ; Peter Kovar ; Eric Johnson ; Chang Park ; Russell Judge ; Saul Rosenberg ; Thomas Sowin ; Nan-Horng Lin
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：April 5, 2007
• 年：2007
• 卷：50
• 期：7
• 页码：1514 - 1527
• 全文大小：419K
• 年卷期：v.50,no.7(April 5, 2007)
• ISSN：1520-4804

文摘

Based on the crystallographic analysis of a urea-checkpoint kinase 1 (Chk1) complex and molecularmodeling, a class of macrocyclic Chk1 inhibitors were designed and their biological activities were evaluated.An efficient synthetic methodology for macrocyclic ureas was developed with Grubbs metathesismacrocyclization as the key step. The structure-activity relationship studies demonstrated that themacrocyclization retains full Chk1 inhibition activity and that the 4-position of the phenyl ring can toleratea wide variety of substituents. These novel Chk1 inhibitors exhibit excellent selectivity over a panel ofmore than 70 kinases. Compounds 5b, 5c, 5f, 15, 16d, 17g, 17h, 17k, 18d, and 22 were identified as idealChk1 inhibitors, which showed little or no single-agent activity but significantly potentiate the cytotoxicitiesof the DNA-damaging antitumor agents doxorubicin and camptothecin. These novel Chk1 inhibitors abrogatethe doxorubicin-induced G2 and camptothecin-induced S checkpoint arrests, confirming that their potentbiological activities are mechanism-based through Chk1 inhibition.