Exploring the Potential of Sulfur Moieties in Compounds Inhibiting Steroidogenesis

  • Biomolecules. 2023 Sep 5;13(9):1349. doi: 10.3390/biom13091349.
Tomasz M Wróbel  1  2 ,  Katyayani Sharma  3  4  5 ,  Iole Mannella  6 ,  Simonetta Oliaro-Bosso  6 ,  Patrycja Nieckarz  1 ,  Therina Du Toit  3  4 ,  Clarissa Daniela Voegel  4  7 ,  Maria Natalia Rojas Velazquez  3  4  5 ,  Jibira Yakubu  3  4  5 ,  Anna Matveeva  3  4  5 ,  Søren Therkelsen  2 ,  Flemming Steen Jørgensen  2 ,  Amit V Pandey  3  4 ,  Agnese C Pippione  6 ,  Marco L Lolli  6 ,  Donatella Boschi  6 ,  Fredrik Björkling  2
Affiliations
  • 1. Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Medical University of Lublin, Chodźki 4a, 20093 Lublin, Poland.
  • 2. Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 160, 2100 Copenhagen, Denmark.
  • 3. Department of Pediatrics, Division of Endocrinology, Diabetology and Metabolism, University Children's Hospital, University of Bern, 3010 Bern, Switzerland.
  • 4. Translational Hormone Research Program, Department of Biomedical Research, University of Bern, 3010 Bern, Switzerland.
  • 5. Graduate School for Cellular and Biomedical Sciences, University of Bern, 3012 Bern, Switzerland.
  • 6. Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy.
  • 7. Department of Nephrology and Hypertension, University Hospital Inselspital, University of Bern, 3010 Bern, Switzerland.
PMID: 37759751 DOI: 10.3390/biom13091349
Abstract

This study reports on the synthesis and evaluation of novel compounds replacing the nitrogen-containing heterocyclic ring on the chemical backbone structure of Cytochrome P450 17α-hydroxylase/12,20-lyase (CYP17A1) inhibitors with a phenyl bearing a sulfur-based substituent. Initial screening revealed compounds with marked inhibition of CYP17A1 activity. The selectivity of compounds was thereafter determined against Cytochrome P450 21-hydroxylase, Cytochrome P450 3A4, and Cytochrome P450 oxidoreductase. Additionally, the compounds showed weak inhibitory activity against aldo-keto reductase 1C3 (AKR1C3). The compounds' impact on steroid hormone levels was also assessed, with some notable modulatory effects observed. This work paves the way for developing more potent dual inhibitors specifically targeting CYP17A1 and AKR1C3.

Keywords
AKR1C3; CYP17A1; enzyme inhibition; prostate cancer.
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