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Titel: 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
VerfasserIn: Mohamed, Abdelrahman
Salah, Mohamed
Tahoun, Mariam
Hawner, Manuel
Abdelsamie, Ahmed S.
Frotscher, Martin
Sprache: Englisch
Titel: Journal of Medicinal Chemistry
Bandnummer: 65
Heft: 17
Seiten: 11726-11744
Verlag/Plattform: ACS
Erscheinungsjahr: 2022
DDC-Sachgruppe: 500 Naturwissenschaften
Dokumenttyp: Journalartikel / Zeitschriftenartikel
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.
DOI der Erstveröffentlichung: 10.1021/acs.jmedchem.2c00589
URL der Erstveröffentlichung: https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c00589
Link zu diesem Datensatz: urn:nbn:de:bsz:291--ds-433864
hdl:20.500.11880/38906
http://dx.doi.org/10.22028/D291-43386
ISSN: 1520-4804
0022-2623
Datum des Eintrags: 7-Nov-2024
Bezeichnung des in Beziehung stehenden Objekts: Supporting Information
In Beziehung stehendes Objekt: https://pubs.acs.org/doi/suppl/10.1021/acs.jmedchem.2c00589/suppl_file/jm2c00589_si_001.pdf
https://pubs.acs.org/doi/suppl/10.1021/acs.jmedchem.2c00589/suppl_file/jm2c00589_si_002.csv
Fakultät: NT - Naturwissenschaftlich- Technische Fakultät
Fachrichtung: NT - Pharmazie
Professur: NT - Prof. Dr. Christian Ducho
NT - Prof. Dr. Rolf W. Hartmann
Sammlung:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

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