Synthesis of Potent Oxindole CDK2 Inhibitors

Bioorg Med Chem. 2003 Apr 17;11(8):1873-81. doi: 10.1016/s0968-0896(03)00036-1.

Abstract

A series of oxindole CDK2 inhibitors was synthesized. These novel analogues have a saturated monosubstituted cyclic moiety at their C-4 position that mimics the ribofuranoside of ATP. This substitution afforded agents with increased potency relative to the parent indolinone and nanomolar range IC(50) against the CDK2 enzyme and two cancer cell lines.

MeSH terms

  • Adenosine Triphosphate / analogs & derivatives
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Binding, Competitive
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / enzymology
  • CDC2-CDC28 Kinases / antagonists & inhibitors*
  • CDC2-CDC28 Kinases / genetics
  • CDC2-CDC28 Kinases / metabolism
  • Cell Division / drug effects
  • Colonic Neoplasms / drug therapy
  • Colonic Neoplasms / enzymology
  • Cyclin E / metabolism
  • Cyclin-Dependent Kinase 2
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Inhibitory Concentration 50
  • Mice
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Ribose / analogs & derivatives
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Cyclin E
  • Enzyme Inhibitors
  • Indoles
  • Recombinant Proteins
  • Ribose
  • Adenosine Triphosphate
  • CDC2-CDC28 Kinases
  • CDK2 protein, human
  • Cdk2 protein, mouse
  • Cyclin-Dependent Kinase 2