Discovery of novel 2-piperidinol-3-(arylsulfonyl)quinoxalines as phosphoinositide 3-kinase α (PI3Kα) inhibitors

Bioorg Med Chem. 2012 May 1;20(9):2837-44. doi: 10.1016/j.bmc.2012.03.026. Epub 2012 Mar 17.

Abstract

A series of novel 2-aliphatic cyclic amine-3-(arylsulfonyl)quinoxalines was synthesized based on the structural features of a previously identified lead, WR1. The 2-piperidinol-3-(arylsulfonyl)quinoxalines, which showed excellent antitumor activities against five human cell lines, with inhibitory activities ranging from 0.34 to 2.32 μM, proved to be a promising class of novel PI3Kα inhibitors. The most potent compound 10d (WR23) showed an inhibitory IC(50) value of 0.025μM against PI3Kα and significant pAkt suppression effect. Molecular docking analysis was performed to determine possible binding modes between PI3Kα and target compounds.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Binding Sites
  • Catalytic Domain
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Computer Simulation
  • Drug Evaluation, Preclinical
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Piperidines / chemistry*
  • Piperidines / pharmacology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Quinoxalines / chemical synthesis
  • Quinoxalines / chemistry*
  • Quinoxalines / pharmacology
  • Structure-Activity Relationship

Substances

  • 2-(piperidin-4-ol)-3-(4-bromophenylsulfonyl)quinoxaline
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Phosphoinositide-3 Kinase Inhibitors
  • Piperidines
  • Quinoxalines
  • Proto-Oncogene Proteins c-akt