Design, Synthesis and SAR in 2,4,7-Trisubstituted Pyrido[3,2- d]Pyrimidine Series as Novel PI3K/mTOR Inhibitors

Molecules. 2021 Sep 2;26(17):5349. doi: 10.3390/molecules26175349.

Abstract

This work describes the synthesis, enzymatic activities on PI3K and mTOR, in silico docking and cellular activities of various uncommon 2,4,7 trisubstituted pyrido[3,2-d]pyrimidines. The series synthesized offers a chemical diversity in C-7 whereas C-2 (3-hydroxyphenyl) and C-4 groups (morpholine) remain unchanged, in order to provide a better understanding of the molecular determinants of PI3K selectivity or dual activity on PI3K and mTOR. Some C-7 substituents were shown to improve the efficiency on kinases compared to the 2,4-di-substituted pyrimidopyrimidine derivatives used as references. Six novel derivatives possess IC50 values on PI3Kα between 3 and 10 nM. The compounds with the best efficiencies on PI3K and mTOR induced micromolar cytotoxicity on cancer cell lines possessing an overactivated PI3K pathway.

Keywords: PI3K and mTOR kinase inhibition; cell effects; molecular modeling; pyridopyrimidine; synthesis.

MeSH terms

  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Structure-Activity Relationship
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Protein Kinase Inhibitors
  • Pyridines
  • Pyrimidines
  • pyrido(3,2-d)pyrimidine
  • MTOR protein, human
  • TOR Serine-Threonine Kinases