Design, synthesis, and biological activity of 5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-one-based potent and selective Chk-1 inhibitors.
J Med Chem
; 50(17): 4162-76, 2007 Aug 23.
Article
de En
| MEDLINE
| ID: mdl-17658776
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.
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Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Protein kinases
/
Azépines
/
Benzodiazépinones
/
Inhibiteurs de protéines kinases
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Antinéoplasiques
Limites:
Animals
/
Humans
Langue:
En
Journal:
J Med Chem
Sujet du journal:
QUIMICA
Année:
2007
Type de document:
Article
Pays d'affiliation:
États-Unis d'Amérique