Design, Synthesis, and Biological Activity of 5,10-Dihydro-dibenzo[b,e][1,4]diazepin-11-one-Based Potent and Selective Chk-1 Inhibitors

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• 作者：Le Wang ; Gerard M. Sullivan ; Laura A. Hexamer ; Lisa A. Hasvold ; Reema Thalji ; Magdalena Przytulinska ; Zhi-Fu Tao ; Gaoquan Li ; Zehan Chen ; Zhan Xiao ; Wen-Zhen Gu ; John Xue ; Mai-Ha Bui ; Philip Merta ; Pe
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：August 23, 2007
• 年：2007
• 卷：50
• 期：17
• 页码：4162 - 4176
• 全文大小：411K
• 年卷期：v.50,no.17(August 23, 2007)
• ISSN：1520-4804

文摘

A novel series of 5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-ones have been synthesized as potent andselective checkpoint kinase 1 (Chk1) inhibitors via structure-based design. Aided by protein X-raycrystallography, medicinal chemistry efforts led to the identification of compound 46d, with potent enzymaticactivity against Chk1 kinase. While maintaining a low cytotoxicity of its own, compound 46d exhibited astrong ability to abrogate G2 arrest and increased the cytotoxicity of camptothecin by 19-fold against SW620cells. Pharmacokinetic studies revealed that it had a moderate bioavailabilty of 20% in mice. Two importantbinding interactions between compound 46b and Chk1 kinase, revealed by X-ray cocrystal structure, werehydrogen bonds between the hinge region and the amide bond of the core structure and a hydrogen bondbetween the methoxy group and Lys38 of the protein.