20-Aminosteroids as a novel class of selective and complete androgen receptor antagonists and inhibitors of prostate cancer cell growth

Bioorg Med Chem. 2010 Oct 1;18(19):6960-9. doi: 10.1016/j.bmc.2010.08.029. Epub 2010 Aug 19.

Abstract

Here, the synthesis and the evaluation of novel 20-aminosteroids on androgen receptor (AR) activity is reported. Compounds 11 and 18 of the series inhibit both the wild type and the T877A mutant AR-mediated transactivation indicating AR antagonistic function. Interestingly, minor structural changes such as stereoisomers of the amino lactame moiety exhibit preferences for antagonism among wild type and mutant AR. Other tested nuclear receptors are only weakly or not affected. In line with this, the prostate cancer cell growth of androgen-dependent but not of cancer cells lacking expression of the AR is inhibited. Further, the expression of the prostate specific antigen used as a diagnostic marker is also repressed. Finally steroid 18 enhances cellular senescence that might explain in part the growth inhibition mediated by this derivative. Steroids 11 and 18 are the first steroids that act as complete AR antagonists and exhibit AR specificity.

MeSH terms

  • Androgen Receptor Antagonists / chemical synthesis
  • Androgen Receptor Antagonists / chemistry
  • Androgen Receptor Antagonists / pharmacology*
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Biomarkers, Tumor / antagonists & inhibitors
  • Biomarkers, Tumor / genetics
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Screening Assays, Antitumor
  • Humans
  • Male
  • Molecular Conformation
  • Mutation
  • Prostate-Specific Antigen / antagonists & inhibitors
  • Prostate-Specific Antigen / genetics
  • Prostatic Neoplasms / diagnosis
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology*
  • RNA, Messenger / antagonists & inhibitors
  • RNA, Messenger / genetics
  • Receptors, Androgen / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stereoisomerism
  • Steroids / chemical synthesis
  • Steroids / chemistry
  • Steroids / pharmacology*
  • Structure-Activity Relationship

Substances

  • Androgen Receptor Antagonists
  • Antineoplastic Agents
  • Biomarkers, Tumor
  • RNA, Messenger
  • Receptors, Androgen
  • Steroids
  • Prostate-Specific Antigen