Synthesis and biological activity of N-aryl-2-aminothiazoles: potent pan inhibitors of cyclin-dependent kinases

Bioorg Med Chem Lett. 2004 Jun 7;14(11):2973-7. doi: 10.1016/j.bmcl.2004.02.105.

Abstract

N-Aryl aminothiazoles 6-9 were prepared from 2-bromothiazole 5 and found to be CDK inhibitors. In cells they act as potent cytotoxic agents. Selectivity for CDK1, CDK2, and CDK4 was dependent of the nature of the N-aryl group and distinct from the CDK2 selective N-acyl analogues. The N-2-pyridyl analogues 7 and 19 showed pan CDK inhibitory activity. Elaborated analogues 19 and 23 exhibited anticancer activity in mice against P388 murine leukemia. The solid-state structure of 7 bound to CDK2 shows a similar binding mode to the N-acyl analogues.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology
  • Inhibitory Concentration 50
  • Leukemia / drug therapy
  • Mice
  • Neoplasms, Experimental / drug therapy
  • Protein Binding
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis
  • Thiazoles / pharmacology*
  • Treatment Outcome

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Thiazoles
  • Cyclin-Dependent Kinases