Synthesis and evaluation of new 2-chloro-4-aminopyrimidine and 2,6-dimethyl-4-aminopyrimidine derivatives as tubulin polymerization inhibitors

Bioorg Med Chem Lett. 2018 Jun 1;28(10):1769-1775. doi: 10.1016/j.bmcl.2018.04.026. Epub 2018 Apr 12.

Abstract

Eighteen new 2-chloro-4-aminopyrimidine and 2,6-dimethyl-4-aminopyrimidine derivatives were synthesized and evaluated as tubulin polymerization inhibitor for the treatment of cancer. Among them, compounds 10, 17, 20 and 21 exhibited potent antiproliferative activities against five human cancer cell lines. Microtubule dynamics assay showed that compound 17 could effectively inhibit tubulin polymerization. Molecular docking studies were also carried out to understand the binding pattern. Further mechanism studies revealed that 17 could induce G2/M phase arrest, disrupt the organization of the cellular microtubule network and induce cell apoptosis and mitochondrial dysfunction.

Keywords: Antiproliferative activity; Design and synthesis; Mechanism; Tubulin polymerization inhibitors.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Microtubules / drug effects
  • Microtubules / metabolism
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Molecular Docking Simulation
  • Molecular Structure
  • Polymerization / drug effects
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Structure-Activity Relationship
  • Tubulin / metabolism*
  • Tubulin Modulators / chemical synthesis
  • Tubulin Modulators / chemistry
  • Tubulin Modulators / pharmacology*

Substances

  • 2,6-dimethyl-4-aminopyrimidine
  • 2-chloro-4-aminopyrimidine
  • Antineoplastic Agents
  • Pyrimidines
  • Tubulin
  • Tubulin Modulators