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

摘要: 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 compound 46d, with enzymatic activity against Chk1 kinase. While maintaining a low cytotoxicity its own, 46d exhibited strong ability abrogate G2 arrest increased camptothecin 19-fold SW620 cells. Pharmacokinetic studies revealed that it had moderate bioavailabilty 20% in mice. Two important binding interactions between 46b kinase, cocrystal structure, were hydrogen bonds hinge region amide bond core structure methoxy group Lys38 protein.