Synthesis of novel galeterone derivatives and evaluation of their in vitro activity against prostate cancer cell lines

Eur J Med Chem. 2019 Oct 1:179:483-492. doi: 10.1016/j.ejmech.2019.06.040. Epub 2019 Jun 18.

Abstract

Prostate cancer is one of the main causes of male cancer-related deaths worldwide and the suppression of androgen receptor signalling is established as an effective strategy for the treatment. A series of galeterone analogues including several steroid-fused azacycles, as well as 17-(benzimidazol-1-ylimino), 16α-(benzimidazol-2-ylamino), and 16α-(benzothiazol-2-ylamino) steroid derivatives, were synthesized and tested against prostate cancer cell lines. Candidate compound 3f was shown to reduce AR-regulated transcription in a dose-dependent manner in nanomolar ranges and suppress expression of AR-regulated proteins Nkx3.1 and PSA in 22Rv1-ARE14 and VCaP cancer cell lines. Flexible docking study revealed similar position of 3f within AR binding site in comparison of galeterone even with stronger binding energy.

Keywords: Galeterone; Prostate; Steroid.

MeSH terms

  • Androstadienes / chemical synthesis
  • Androstadienes / chemistry
  • Androstadienes / pharmacology*
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology*
  • Cell Line
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Male
  • Molecular Structure
  • PC-3 Cells
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Structure-Activity Relationship

Substances

  • Androstadienes
  • Antineoplastic Agents
  • Benzimidazoles
  • 3-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene