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

doi:10.3390/biom13091349

Biomolecules (Sep 2023)

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

DOI: https://doi.org/10.3390/biom13091349
Journal volume & issue: Vol. 13, no. 9
p. 1349

Abstract

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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.

Published in Biomolecules

ISSN: 2218-273X (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Science: Microbiology
Website: https://www.mdpi.com/journal/biomolecules

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