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

Authors :
Wang L
Sullivan GM
Hexamer LA
Hasvold LA
Thalji R
Przytulinska M
Tao ZF
Li G
Chen Z
Xiao Z
Gu WZ
Xue J
Bui MH
Merta P
Kovar P
Bouska JJ
Zhang H
Park C
Stewart KD
Sham HL
Sowin TJ
Rosenberg SH
Lin NH
Source :
Journal of medicinal chemistry [J Med Chem] 2007 Aug 23; Vol. 50 (17), pp. 4162-76. Date of Electronic Publication: 2007 Jul 21.
Publication Year :
2007

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 increased the cytotoxicity of camptothecin by 19-fold against SW620 cells. Pharmacokinetic studies revealed that it had a moderate bioavailabilty of 20% in mice. Two important binding interactions between compound 46b and Chk1 kinase, revealed by X-ray cocrystal structure, were hydrogen bonds between the hinge region and the amide bond of the core structure and a hydrogen bond between the methoxy group and Lys38 of the protein.

Details

Language :
English
ISSN :
0022-2623
Volume :
50
Issue :
17
Database :
MEDLINE
Journal :
Journal of medicinal chemistry
Publication Type :
Academic Journal
Accession number :
17658776
Full Text :
https://doi.org/10.1021/jm070105d