Identification of a new series of flavopiridol-like structures as kinase inhibitors with high cytotoxic potency

Eur J Med Chem. 2020 Aug 1:199:112355. doi: 10.1016/j.ejmech.2020.112355. Epub 2020 May 5.

Abstract

In this work, unique flavopiridol analogs bearing thiosugars, amino acids and heterocyclic moieties tethered to the flavopiridol via thioether and amine bonds mainly on its C ring have been prepared. The analogs bearing thioether-benzimidazoles as substituents have demonstrated high cytotoxic activity in vitro against up to seven cancer cell lines. Their cytotoxic effects are comparable to those of flavopiridol. The most active compound 13c resulting from a structure-activity relationship (SAR) study and in silico docking showed the best antiproliferative activity and was more efficient than the reference compound. In addition, compound 13c showed significant nanomolar inhibition against CDK9, CDK10, and GSK3β protein kinases.

Keywords: CDK10; CDK9; Cytotoxicity; Kinase inhibitors; Kinases; Structure-activity relationship.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Flavonoids / chemical synthesis
  • Flavonoids / chemistry
  • Flavonoids / pharmacology*
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Piperidines / chemical synthesis
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinases / metabolism*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Flavonoids
  • Piperidines
  • Protein Kinase Inhibitors
  • alvocidib
  • Protein Kinases