Novel androgen receptor full antagonists: Design, synthesis, and a docking study of glycerol and aminoglycerol derivatives that contain p-carborane cages

Bioorg Med Chem. 2018 Jul 30;26(13):3805-3811. doi: 10.1016/j.bmc.2018.06.007. Epub 2018 Jun 7.

Abstract

Based on the co-crystal structure of bicalutamide with a T877A-mutated androgen receptor (AR), glycerol and aminoglycerol derivatives were designed and synthesized as a novel type of carborane-containing AR modulators. The (R)-isomer of 6c, whose chirality is derived from the glycerol group, showed 20 times more potent cell inhibitory activity against LNCaP cell lines expressing T877A-mutated AR than the corresponding (S)-isomer. Docking studies of both isomers with AR suggested that (R)-6c is in closer spatial proximity to helix-12 of the AR than (S)-6c, which is the most important common motif in the secondary structure of AR for the expression of antagonistic activity.

Keywords: Androgen receptor; Anti-androgen withdrawal syndrome; Carborane; Hydrophobic pharmacophore.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgen Receptor Antagonists / chemical synthesis*
  • Androgen Receptor Antagonists / metabolism
  • Androgen Receptor Antagonists / pharmacology
  • Binding Sites
  • Boranes / chemistry*
  • Catalytic Domain
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Design*
  • Glycerol / chemistry*
  • Glycerol / metabolism
  • Glycerol / pharmacology
  • Humans
  • Molecular Docking Simulation
  • Mutagenesis, Site-Directed
  • Receptors, Androgen / chemistry
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism*
  • Stereoisomerism

Substances

  • Androgen Receptor Antagonists
  • Boranes
  • Receptors, Androgen
  • Glycerol