Synthesis and biological evaluation of pyrido[3',2':4,5]furo[3,2-d]pyrimidine derivatives as novel PI3 kinase p110alpha inhibitors

Bioorg Med Chem Lett. 2007 May 1;17(9):2438-42. doi: 10.1016/j.bmcl.2007.02.032. Epub 2007 Feb 15.


4-Morpholin-4-ylpyrido[3',2':4,5]thieno[3,2-d]pyrimidine 2a was discovered in our chemical library as a novel p110alpha inhibitor with an IC(50) of 1.4 microM. By structural modification of 2a, the 2-aryl-4-morpholinopyrido[3',2':4,5]furo[3,2-d]pyrimidine derivative 10e was discovered as a p110alpha inhibitor with approximately 400-fold greater potency than 2a. Evaluation of isoform selectivity showed that 10e is a potent inhibitor of p110beta. Furthermore, 10e showed anti-proliferative activity in various cell lines, including multi-drug resistant MCF7/ADR-res cells, and was effective against HeLa human cervical tumor xenografts in nude mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Chemistry, Pharmaceutical / methods
  • Class I Phosphatidylinositol 3-Kinases
  • Drug Design
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • HeLa Cells
  • Humans
  • Inhibitory Concentration 50
  • Mice
  • Molecular Conformation
  • Neoplasm Transplantation
  • Phosphoinositide-3 Kinase Inhibitors*
  • Pyridines / chemical synthesis*
  • Pyrimidines / chemical synthesis*


  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Phosphoinositide-3 Kinase Inhibitors
  • Pyridines
  • Pyrimidines
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CB protein, human