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Discovery of 4′-(1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-benzonitriles and 4′-(1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-pyridine-2′-carbonitriles as potent checkpoint kinase 1 (Chk1) inhibitors by Zhi-Fu Tao; Gaoquan Li; Yunsong Tong; Kent D. Stewart; Zehan Chen; Mai-Ha Bui; Philip Merta; Chang Park; Peter Kovar; Haiying Zhang; Hing L. Sham; Saul H. Rosenberg; Thomas J. Sowin; Nan-Horng Lin is a Biochemistry, Genetics and Molecular Biology article available to read on EtoBox.

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An extensive structure-activity relationship study of the 3-position of a series of tricyclic pyrazole-based Chk1 inhibitors is described. As a result, 4'-(1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-benzonitriles (4) and 4'-(1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-pyridine-2'-carbonitriles (29) emerged as new lead series. Compared with the original lead compound 2, these new leads fully retain the biological activity in both enzymatic inhibition and cell-based assays. More importantly, the new leads 4 and 29 exhibit favorable physicochemical properties such as lower molecular weight, lower Clog P, and the absence of a hydroxyl group. Furthermore, structure-activity relationship studies were performed at the 6- and 7-positions of 4, which led to the identification of ideal Chk1 inhibitors 49, 50, 51, and 55. These compounds not only potently inhibit Chk1 in an enzymatic assay but also significantly potentiate the cytotoxicity of DNA-damaging agents in cell-based assays while they show little single agent activity. A cell cycle analysis by FACS confirmed that these Chk1 inhibitors efficiently abrogate the G2/M and S checkpoints induced by DNA-damaging agent. The current work paved the way

Who reads Discovery of 4′-(1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-benzonitriles and 4′-(1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-pyridine-2′-carbonitriles as potent checkpoint kinase 1 (Chk1) inhibitors?

Author

Zhi-Fu Tao; Gaoquan Li; Yunsong Tong; Kent D. Stewart; Zehan Chen; Mai-Ha Bui; Philip Merta; Chang Park; Peter Kovar; Haiying Zhang; Hing L. Sham; Saul H. Rosenberg; Thomas J. Sowin; Nan-Horng Lin

Publisher

Elsevier Science; Elsevier ; Elsevier Ltd.; Elsevier BV (ISSN 0960-894X)

Published

2007

Language

EN

Field

Biochemistry, Genetics and Molecular Biology (Life Sciences)