Synthesis of quinolinyl/isoquinolinyl[a]pyrrolo [3,4-c] carbazoles as cyclin D1/CDK4 inhibitors

Bioorg Med Chem Lett. 2003 Apr 7;13(7):1231-5. doi: 10.1016/s0960-894x(03)00133-1.

Abstract

A novel series of pyrrolo[3,4-c] carbazoles fused with a quinolinyl/isoquinolinyl moiety were synthesized and their D1/CDK4 inhibitory and antiproliferative activity were evaluated. Compound 8H, 14H-isoquinolinyl[6,5-a]-pyrrolo[3,4-c]carbazole-7,9-dione (1d) was found to be a highly potent D1/CDK4 inhibitor with an IC(50) of 69 nM. Compound 1d also inhibited tumor cell growth, arrested tumor cells in G1 phase and inhibited pRb phosphorylation.

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology*
  • Carbazoles / chemical synthesis*
  • Carbazoles / pharmacology*
  • Cell Cycle
  • Crystallography, X-Ray
  • Cyclin D1 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • Cyclization
  • Dimethyl Sulfoxide
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Kinetics
  • Phosphorylation
  • Proto-Oncogene Proteins*
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Carbazoles
  • Enzyme Inhibitors
  • Proto-Oncogene Proteins
  • Cyclin D1
  • CDK4 protein, human
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinases
  • Dimethyl Sulfoxide