Design, Synthesis, and Biological Activity of 5,10-Dihydro-dibenzo[b,e][1,4]diazepin-11-one-Based Potent and Selective Chk-1 Inhibitors
| Autor: | Magdalena Przytulinska, Gaoquan Li, Thomas J. Sowin, Wen-Zhen Gu, Lisa A. Hasvold, Philip Merta, Zhan Xiao, Le Wang, John Xue, Reema Thalji, Kent D. Stewart, Zehan Chen, Zhi-Fu Tao, Nan-Horng Lin, Jennifer J. Bouska, Chang Park, Hexamer Laura, Hing L. Sham, Haiying Zhang, Mai-Ha Bui, Gerard M. Sullivan, Saul H. Rosenberg, Peter Kovar |
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| Rok vydání: | 2007 |
| Předmět: |
Models
Molecular Stereochemistry Biological Availability Antineoplastic Agents Crystallography X-Ray Mice Structure-Activity Relationship chemistry.chemical_compound Cell Line Tumor Drug Discovery medicine Animals Humans Peptide bond Structure–activity relationship CHEK1 Cytotoxicity Protein Kinase Inhibitors Benzodiazepinones biology Chemistry Drug Synergism Biological activity Azepines Doxorubicin Enzyme inhibitor Drug Design Checkpoint Kinase 1 Lactam biology.protein Molecular Medicine Camptothecin Protein Kinases Protein Binding medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 50:4162-4176 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm070105d |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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