Exploring the Potential of Sulfur Moieties in Compounds Inhibiting Steroidogenesis

Biomolecules. 2023 Sep 5;13(9):1349. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Nitrogen*
  • Secondary Metabolism
  • Sulfur*

Substances

  • Nitrogen
  • Sulfur

Grants and funding

T.M.W. research is funded by the Narodowe Centrum Nauki grant Sonata 2020/39/D/NZ7/00572. A.V.P. acknowledges SWISS NATIONAL SCIENCE FOUNDATION, grant number 310030M_204518 and CANCER RESEARCH SWITZERLAND grant number KFS-5557-02-2022. J.Y., M.N.R.V., and K.S. are funded by the SWISS GOVERNMENT EXCELLENCE SCHOLARSHIP (ESKAS) grant numbers 2022.0470, 2020.0557, and 2019.0385. T.d.T. is funded by the Marie Skłodowska-Curie Individual Fellowship (#101023999). I.M., S.O.B., M.L.L., and D.B. acknowledge Fondazione CRT (grant OLIS_CRT_22_01) and A.C.P. acknowledges the University of Torino (grant PIPA_GFI_22_01_F).