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.
Radek Jorda  1 ,  Eva Řezníčková  2 ,  Urszula Kiełczewska  3 ,  Jadwiga Maj  3 ,  Jacek W Morzycki  3 ,  Leszek Siergiejczyk  3 ,  Václav Bazgier  4 ,  Karel Berka  5 ,  Lucie Rárová  2 ,  Agnieszka Wojtkielewicz  6
Affiliations
  • 1. Laboratory of Growth Regulators, The Czech Academy of Sciences, Institute of Experimental Botany & Palacký University, Šlechtitelů 27, 783 71, Olomouc, Czech Republic. Electronic address: [email protected].
  • 2. Laboratory of Growth Regulators, The Czech Academy of Sciences, Institute of Experimental Botany & Palacký University, Šlechtitelů 27, 783 71, Olomouc, Czech Republic.
  • 3. Institute of Chemistry, University of Białystok, K. Ciołkowskiego 1K, 15-245, Białystok, Poland.
  • 4. Department of Chemical Biology and Genetics, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacky University & Institute of Experimental Botany ASCR, Šlechtitelů 27, 78371, Olomouc, Czech Republic; Department of Physical Chemistry, Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacky University, 17. listopadu 12, 771 46, Olomouc, Czech Republic.
  • 5. Department of Physical Chemistry, Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacky University, 17. listopadu 12, 771 46, Olomouc, Czech Republic.
  • 6. Institute of Chemistry, University of Białystok, K. Ciołkowskiego 1K, 15-245, Białystok, Poland. Electronic address: [email protected].
PMID: 31271960 DOI: 10.1016/j.ejmech.2019.06.040
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.