Synthesis and evaluation of 5-substituted 9-hydroxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones as check point 1 kinase inhibitors

Bioorg Med Chem. 2010 Nov 15;18(22):7878-89. doi: 10.1016/j.bmc.2010.09.042. Epub 2010 Sep 22.

Abstract

The structure-activity relationship (SAR) of 5-substituted pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione derivatives 5 was investigated for their potential as Chk1 inhibitors for possible chemo- and radio-potentiators in anticancer chemotherapies. In silico virtual screening helped to optimize the substituent on the phenyl ring, and led to identification of the m-carbamoyl group among the 117 analogues tested. Further optimization studies focusing on the docking model of 15 in the active site of Chk1 revealed that 32b (IC(50)=2.8nM) was a more potent inhibitor than UNC-01.

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Binding Sites
  • Carbazoles / chemical synthesis
  • Carbazoles / chemistry*
  • Carbazoles / pharmacology
  • Catalytic Domain
  • Cell Line, Tumor
  • Checkpoint Kinase 1
  • Computer Simulation
  • Humans
  • Phthalimides / chemical synthesis*
  • Phthalimides / chemistry
  • Phthalimides / pharmacology
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinases / chemistry*
  • Protein Kinases / metabolism
  • Pyrroles / chemistry
  • Structure-Activity Relationship

Substances

  • 5-(3-(2-(guanidino)ethylcarbamoyl)benzylaminocarboyl)-9-hydroxy-1,3-dihydropyrrolo(3,4-c)carbazole-1,3(2H,6H)-dione
  • Antineoplastic Agents
  • Carbazoles
  • Phthalimides
  • Protein Kinase Inhibitors
  • Pyrroles
  • Protein Kinases
  • CHEK1 protein, human
  • Checkpoint Kinase 1