Design, synthesis, and biological activity of 5, 10-dihydro-dibenzo [b, e][1, 4] diazepin-11-one-based potent and selective Chk-1 inhibitors

…, LA Hasvold, R Thalji, M Przytulinska…

Index: Wang, Le; Sullivan, Gerard M.; Hexamer, Laura A.; Hasvold, Lisa A.; Thalji, Reema; Przytulinska, Magdalena; Tao, Zhi-Fu; Li, Gaoquan; Chen, Zehan; Xiao, Zhan; Gu, Wen-Zhen; Xue, John; Bui, Mai-Ha; Merta, Philip; Kovar, Peter; Bouska, Jennifer J.; Zhang, Haiying; Park, Chang; Stewart, Kent D.; Sham, Hing L.; Sowin, Thomas J.; Rosenberg, Saul H.; Lin, Nan-Horng Journal of Medicinal Chemistry, 2007 , vol. 50, # 17 p. 4162 - 4176

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Citation Number: 37

Abstract

A novel series of 5, 10-dihydro-dibenzo [b, e][1, 4] diazepin-11-ones have been synthesized as potent and selective checkpoint kinase 1 (Chk1) inhibitors via structure-based design. Aided by protein X-ray crystallography, medicinal chemistry efforts led to the identification of compound 46d, with potent enzymatic activity against Chk1 kinase. While maintaining a low cytotoxicity of its own, compound 46d exhibited a strong ability to abrogate G2 arrest and ...