Exploring the Potential of Sulfur Moieties in Compounds Inhibiting Steroidogenesis
Tomasz M. Wróbel,
Katyayani Sharma,
Iole Mannella,
Simonetta Oliaro-Bosso,
Patrycja Nieckarz,
Therina Du Toit,
Clarissa Daniela Voegel,
Maria Natalia Rojas Velazquez,
Jibira Yakubu,
Anna Matveeva,
Søren Therkelsen,
Flemming Steen Jørgensen,
Amit V. Pandey,
Agnese C. Pippione,
Marco L. Lolli,
Donatella Boschi,
Fredrik Björkling
Affiliations
Tomasz M. Wróbel
Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Medical University of Lublin, Chodźki 4a, 20093 Lublin, Poland
Katyayani Sharma
Department of Pediatrics, Division of Endocrinology, Diabetology and Metabolism, University Children’s Hospital, University of Bern, 3010 Bern, Switzerland
Iole Mannella
Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy
Simonetta Oliaro-Bosso
Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy
Patrycja Nieckarz
Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Medical University of Lublin, Chodźki 4a, 20093 Lublin, Poland
Therina Du Toit
Department of Pediatrics, Division of Endocrinology, Diabetology and Metabolism, University Children’s Hospital, University of Bern, 3010 Bern, Switzerland
Clarissa Daniela Voegel
Translational Hormone Research Program, Department of Biomedical Research, University of Bern, 3010 Bern, Switzerland
Maria Natalia Rojas Velazquez
Department of Pediatrics, Division of Endocrinology, Diabetology and Metabolism, University Children’s Hospital, University of Bern, 3010 Bern, Switzerland
Jibira Yakubu
Department of Pediatrics, Division of Endocrinology, Diabetology and Metabolism, University Children’s Hospital, University of Bern, 3010 Bern, Switzerland
Anna Matveeva
Department of Pediatrics, Division of Endocrinology, Diabetology and Metabolism, University Children’s Hospital, University of Bern, 3010 Bern, Switzerland
Søren Therkelsen
Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 160, 2100 Copenhagen, Denmark
Flemming Steen Jørgensen
Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 160, 2100 Copenhagen, Denmark
Amit V. Pandey
Department of Pediatrics, Division of Endocrinology, Diabetology and Metabolism, University Children’s Hospital, University of Bern, 3010 Bern, Switzerland
Agnese C. Pippione
Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy
Marco L. Lolli
Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy
Donatella Boschi
Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy
Fredrik Björkling
Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 160, 2100 Copenhagen, Denmark
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.
