Synthesis and structure-activity relationships of soluble 8-substituted 4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones as inhibitors of the Wee1 and Chk1 checkpoint kinases

Bioorg Med Chem Lett. 2008 Feb 1;18(3):929-33. doi: 10.1016/j.bmcl.2007.12.046. Epub 2008 Jan 11.

Abstract

Pyrrolo[3,4-c]carbazoles bearing solubilising basic side chains at the 8-position retain potent Wee1 and Chk1 inhibitory properties in isolated enzyme assays, and evidence of G2/M checkpoint abrogation in several cellular assays. Co-crystal structure studies confirm that the primary binding to the Wee1 enzyme is as described previously, with the C-8 side chains residing in an area of bulk tolerance.

MeSH terms

  • Carbazoles / chemical synthesis*
  • Carbazoles / chemistry
  • Carbazoles / pharmacology*
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Checkpoint Kinase 1
  • Combinatorial Chemistry Techniques*
  • Humans
  • Molecular Structure
  • Nuclear Proteins / antagonists & inhibitors*
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinases / metabolism*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Carbazoles
  • Cell Cycle Proteins
  • Nuclear Proteins
  • Protein Kinase Inhibitors
  • Protein Kinases
  • Protein-Tyrosine Kinases
  • WEE1 protein, human
  • CHEK1 protein, human
  • Checkpoint Kinase 1