Synthesis and preliminary investigations into novel 1,2,3-triazole-derived androgen receptor antagonists inspired by bicalutamide

Bioorg Med Chem Lett. 2014 Nov 1;24(21):4948-53. doi: 10.1016/j.bmcl.2014.09.036. Epub 2014 Sep 19.

Abstract

A versatile and high yielding synthesis of novel androgen receptor (AR) antagonists is presented. Using this methodology, six 1,4-substituted-1,2,3-triazole derived bicalutamide mimics were synthesised in five steps and in isolated overall yields from 41% to 85%. Evaluation of these compounds for their anti-proliferative properties against androgen dependent (LNCaP) and independent (PC-3) cells showed promising IC50 values of 34-45 μM and 29-151 μM, respectively. The data suggest that the latter compounds may be an excellent starting point for the development of prostate cancer therapeutics for both androgen dependent and independent forms of this disease. Docking of these compounds (each enantiomer) in silico into the T877A mutated androgen receptor, as possessed by LNCaP cells, was also undertaken.

Keywords: Androgen receptor; Bicalutamide; Click chemistry; Molecular modeling; Prostate cancer; Triazole.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgen Antagonists / chemistry*
  • Androgen Antagonists / pharmacology
  • Androgen Receptor Antagonists / chemical synthesis*
  • Androgen Receptor Antagonists / pharmacology*
  • Anilides / chemistry*
  • Anilides / pharmacology
  • Cell Survival / drug effects
  • Humans
  • Male
  • Nitriles / chemistry*
  • Nitriles / pharmacology
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / metabolism
  • Receptors, Androgen / chemistry*
  • Receptors, Androgen / metabolism
  • Tosyl Compounds / chemistry*
  • Tosyl Compounds / pharmacology
  • Triazoles / chemistry*
  • Tumor Cells, Cultured

Substances

  • AR protein, human
  • Androgen Antagonists
  • Androgen Receptor Antagonists
  • Anilides
  • Nitriles
  • Receptors, Androgen
  • Tosyl Compounds
  • Triazoles
  • bicalutamide