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 microM) and enhanced doxorubicin cytotoxicity (IC50=0.44 microM) while displaying no single agent activity.
journal_name
Bioorg Med Chem Lettjournal_title
Bioorganic & medicinal chemistry lettersauthors
Li G,Hasvold LA,Tao ZF,Wang GT,Gwaltney SL 2nd,Patel J,Kovar P,Credo RB,Chen Z,Zhang H,Park C,Sham HL,Sowin T,Rosenberg SH,Lin NHdoi
10.1016/j.bmcl.2006.01.028subject
Has Abstractpub_date
2006-04-15 00:00:00pages
2293-8issue
8eissn
0960-894Xissn
1464-3405pii
S0960-894X(06)00051-5journal_volume
16pub_type
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