Synthesis, In Vitro and In Silico Anticancer Activity of New 4-Methylbenzamide Derivatives Containing 2,6-Substituted Purines as Potential Protein Kinases Inhibitors

Int J Mol Sci. 2021 Nov 25;22(23):12738. doi: 10.3390/ijms222312738.

Abstract

A novel class of potential protein kinase inhibitors 7-16 was synthesized in high yields using various substituted purines. The most promising compounds, 7 and 10, exhibited inhibitory activity against seven cancer cell lines. The IC50 values for compounds 7 and 10 were 2.27 and 2.53 μM for K562 cells, 1.42 and 1.52 μM for HL-60 cells, and 4.56 and 24.77 μM for OKP-GS cells, respectively. In addition, compounds 7 and 10 dose-dependently induced the apoptosis and cell cycle arrest at G2/M phase, preventing the cell division of OKP-GS cells. Compounds 7, 9, and 10 showed 36-45% inhibitory activity against PDGFRα and PDGFRβ at the concentration of 1 μM. Molecular modeling experiments showed that obtained compounds could bind to PDGFRα as either type 1 (compound 7, ATP-competitive) or type 2 (compound 10, allosteric) inhibitors, depending on the substituent in the amide part of the molecule.

Keywords: anticancer activity; cellular apoptosis; molecular docking; protein kinase inhibitors; purine derivatives.

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis
  • Benzamides / chemistry*
  • Cell Cycle
  • Cell Proliferation
  • Computer Simulation
  • Dose-Response Relationship, Drug
  • Humans
  • In Vitro Techniques
  • Molecular Docking Simulation
  • Molecular Structure
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinases / chemistry*
  • Purines / chemistry*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Benzamides
  • Protein Kinase Inhibitors
  • Purines
  • Protein Kinases
  • N-methylbenzamide