Synthesis, EGFR Inhibition and Anti-cancer Activity of New 3,6-dimethyl-1-phenyl-4-(substituted-methoxy)pyrazolo[3,4-d] pyrimidine Derivatives

Anticancer Agents Med Chem. 2017;17(10):1389-1400. doi: 10.2174/1872211311666170213105004.

Abstract

as EGFR inhibitors, mammalian target of rapamycin (mTOR) inhibitors, Src or dual Src/Abl inhibitors, glycogen synthase kinase-3b (GSK-3b) inhibitors or cyclin dependent kinase (CDK) inhibitors.

Objective: A new series of hybrid pyrazolo[3,4-d]pyrimidine scaffold with a heteroaryl moiety as pyrazole, oxadiazole, triazole or phthalimide moiety (14a-f, 16, 17, 19, 20) was synthesized and biologically evaluated for the cytotoxicity against human liver cancer cell line (HEPG-2), human breast cancer cell line (MCF-7) and human colon cancer cell line (HCT-116). Results and Method: While the pyrazolo hybrid compounds (14a-f) showed good activity against HEPG-2, MCF- 7 and HCT-116 cell lines (IC50 = 3.65 - 39.98, 1.45 - 54.19 and 2.00 - 50.6 µM respectively) in comparison with doxorubicin (IC50 = 5.66, 2.60 and 8.48 µM respectively), the triazolo derivatives (17, 19) showed considerable potency (IC50 = 22.20 - 54.61, 14.98 - 88.78, and 10.79 - 53.40 µM respectively), the oxadiazolo hybrid compound (16, IC50 = 149.91, 115.89 and 110.07 µM respectively) and phthalimido hybrid compound (20, IC50 = 96.02, 131.19 and 120.36 µM respectively) showed low potency. The pyrazolo derivative (14d, IC50 = 3.65, 1.45 and 2.00 µM) was the most potent among all compounds against HEPG-2, MCF-7 and HCT-116 cell lines respectively. Also, the hybrid pyrazolo[3,4-d]pyrimidine derivatives were evaluated for their inhibitory activity to epidermal growth factor receptor tyrosine kinase (EGFR-TK) and they showed a good inhibitory activity (IC50 = 8.27 - 19.03 µM). With the exception of the pyrazolo derivative (14c, IC50 = 18.82 µM), the inhibitory activity against EGFR-TK was consistent with the in vitro cytotoxic activity against HEPG-2, MCF-7 and HCT-116 cell lines.

Conclusion: The newly synthesized compounds showed good activity against HEPG-2, MCF-7 and HCT-116 cell lines in comparison with the reference drug doxorubicin.

Keywords: 4-d]pyrimidine; Anti-cancer activity; EGFR inhibition; anticancer screening; cytotoxicity; pyrazolo[3; synthesis.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / metabolism
  • Humans
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • pyrazolo(3,4-d)pyrimidine
  • EGFR protein, human
  • ErbB Receptors