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. 2007 Aug 23;50(17):4162-76. doi: 10.1021/jm070105d. Epub 2007 Jul 21.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Azepines / chemical synthesis*
  • Azepines / chemistry
  • Azepines / pharmacology
  • Benzodiazepinones / chemical synthesis*
  • Benzodiazepinones / chemistry
  • Benzodiazepinones / pharmacology
  • Biological Availability
  • Camptothecin / pharmacology
  • Cell Line, Tumor
  • Checkpoint Kinase 1
  • Crystallography, X-Ray
  • Doxorubicin / pharmacology
  • Drug Design
  • Drug Synergism
  • Humans
  • Mice
  • Models, Molecular
  • Protein Binding
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinases / chemistry
  • Protein Kinases / metabolism*
  • Structure-Activity Relationship

Substances

  • 2-(3-(3-methoxy-4-nitrophenyl)-11-oxo-10,11-dihydro-5H-dibenzo(b,e)(1,4)diazepin-8-yl)-N,N-dimethylacetamide
  • Antineoplastic Agents
  • Azepines
  • Benzodiazepinones
  • Protein Kinase Inhibitors
  • Doxorubicin
  • Protein Kinases
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • Chek1 protein, mouse
  • Camptothecin