Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1374971 | Bioorganic & Medicinal Chemistry Letters | 2006 | 6 Pages |
Abstract
Based on the X-ray crystallography of our lead compound 1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-cyanopyrazin-2-yl)urea in the checkpoint kinase 1 (Chk1) enzyme, we modified R4, and to a lesser extent, R2, and R5 of the phenyl ring, and made a variety of N-aryl-N′-pyrazinylurea Chk1 inhibitors. Enzymatic activity less than 20 nM was observed in 15 of 41 compounds. Compound 8i provided the best overall results in the cellular assays as it abrogated doxorubicin-induced cell cycle arrest (IC50 = 1.7 μM) and enhanced doxorubicin cytotoxicity (IC50 = 0.44 μM) while displaying no single agent activity.
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Physical Sciences and Engineering
Chemistry
Organic Chemistry
Authors
Gaoquan Li, Lisa A. Hasvold, Zhi-Fu Tao, Gary T. Wang, Stephen L. Gwaltney II, Jyoti Patel, Peter Kovar, Robert B. Credo, Zehan Chen, Haiying Zhang, Chang Park, Hing L. Sham, Thomas Sowin, Saul H. Rosenberg, Nan-Horng Lin,