Synthesis and biological evaluation of 4-morpholino-2-phenylquinazolines and related derivatives as novel PI3 kinase p110alpha inhibitors

Bioorg Med Chem. 2006 Oct 15;14(20):6847-58. doi: 10.1016/j.bmc.2006.06.046. Epub 2006 Jul 11.

Abstract

A series of 4-morpholino-2-phenylquinazolines and related derivatives were prepared and evaluated as inhibitors of PI3 kinase p110alpha. In this series, the thieno[3,2-d]pyrimidine derivative 15e showed the strongest inhibitory activity against p110alpha, with an IC(50) value of 2.0 nM, and inhibited proliferation of A375 melanoma cells with an IC(50) value of 0.58 microM. Moreover, 15e was found to be selective for p110alpha over other PI3K isoforms and protein kinases, making it the first example of a selective PI3K p110alpha inhibitor.

MeSH terms

  • Animals
  • Cattle
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chromones / pharmacology
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Molecular Structure
  • Morpholines / chemical synthesis*
  • Morpholines / chemistry
  • Morpholines / pharmacology*
  • Phosphoinositide-3 Kinase Inhibitors*
  • Quinazolines / chemical synthesis*
  • Quinazolines / chemistry
  • Quinazolines / pharmacology*
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Chromones
  • Enzyme Inhibitors
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Quinazolines
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one