N-(indazolyl)benzamido derivatives as CDK1 inhibitors: design, synthesis, biological activity, and molecular docking studies

Arch Pharm (Weinheim). 2009 May;342(5):265-73. doi: 10.1002/ardp.200800159.

Abstract

A series of N-1H-indazole-1-carboxamides has been synthesized and their effects on both CDK1/cyclin B and the K-562 (human chronic myelogenus leukemia) cell line were evaluated. Using a computational model, we have observed that all the most active compounds 9e, f, i-n exhibited the same binding mode of purvanalol A in the ATP-binding cleft. Although they were able to moderately inhibit the leukemic cell line K-562 and to show inhibitory activity against the Cdc2-Cyclin B kinase in the low micromolar range, they turned out to be non-cytotoxic against HuDe (IZSL) primary cell cultures from human derm. These preliminary results are quite encouraging in view of the low toxicity demonstrated by the above-mentioned compounds.

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Benzamides / chemical synthesis*
  • Benzamides / pharmacology
  • Binding Sites
  • CDC2 Protein Kinase / antagonists & inhibitors*
  • CDC2 Protein Kinase / chemistry
  • Cell Proliferation / drug effects
  • Cyclin B / antagonists & inhibitors
  • Drug Design
  • Drug Screening Assays, Antitumor
  • Humans
  • Imidazoles / chemical synthesis*
  • Imidazoles / pharmacology
  • K562 Cells
  • Models, Molecular*
  • Protein Binding
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Benzamides
  • Cyclin B
  • Imidazoles
  • CDC2 Protein Kinase