2. Academic Validation
  3. Dual Targeting of Steroid Sulfatase and 17β-Hydroxysteroid Dehydrogenase Type 1 by a Novel Drug-Prodrug Approach: A Potential Therapeutic Option for the Treatment of Endometriosis

Dual Targeting of Steroid Sulfatase and 17β-Hydroxysteroid Dehydrogenase Type 1 by a Novel Drug-Prodrug Approach: A Potential Therapeutic Option for the Treatment of Endometriosis

  • J Med Chem. 2022 Sep 8;65(17):11726-11744. doi: 10.1021/acs.jmedchem.2c00589.
Abdelrahman Mohamed 1 2,  Mohamed Salah 1 3,  Mariam Tahoun 1,  Manuel Hawner 1,  Ahmed S Abdelsamie 4 5,  Martin Frotscher 1
Affiliations

Affiliations

  • 1 Department of Pharmacy, Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C23, Saarbrücken D-66123, Germany.
  • 2 Pharmaceutical Organic Chemistry Department, Assiut University, Assiut 71526, Egypt.
  • 3 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, October University for Modern Sciences and Arts, Cairo 12451, Egypt.
  • 4 Department of Chemistry of Natural and Microbial Products, Institute of Pharmaceutical and Drug Industries Research, National Research Centre, El-Buhouth St., Dokki, P.O. Box 12622 Cairo 12451, Egypt.
  • 5 Department of Drug Design and Optimization, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), Campus Building E81, Saarbrücken 66123, Germany.
PMID: 35993890 DOI: 10.1021/acs.jmedchem.2c00589
Abstract

A novel approach for the dual inhibition of steroid sulfatase (STS) and 17β-hydroxysteroid dehydrogenase type 1(17β HSD1) by a single drug was explored, starting from in-house 17β HSD1 inhibitors via masking their phenolic OH group with a sulfamate ester. The sulfamates were intentionally designed as drugs for the inhibition of STS and, at the same time, prodrugs for 17β-HSD1 inhibition ("drug-prodrug approach"). The most promising sulfamates 13, 16, 18-20, 22-24, 36, and 37 showed nanomolar IC50 values for STS inhibition in a cellular assay and their corresponding Phenols displayed potent 17β-HSD1 inhibition in cell-free and cellular assays, high selectivity over 17β-HSD2, reasonable metabolic stability, and low Estrogen Receptor α affinity. A close relationship was found between the liberation of the phenolic compound by sulfamate hydrolysis and 17β-HSD1 inactivation. These results showed that the envisaged drug-prodrug concept was successfully implemented. The novel compounds constitute a promising class of therapeutics for the treatment of endometriosis and other estrogen-dependent diseases.

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