Synthesis of substituted 15β-alkoxy estrone derivatives and their cofactor-dependent inhibitory effect on 17β-HSD1
17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) is a key enzyme in the biosynthesis of 17β-estradiol. Novel estrone-based compounds bearing various 15β-oxa-linked substituents and hydroxy, methoxy, benzyloxy, and sulfamate groups in position C3 as potential 17β-HSD1 inhibitors have been synthesiz...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2019-01-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/14756366.2019.1634064 |
| _version_ | 1828772727990779904 |
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| author | Bianka Edina Herman Anita Kiss János Wölfling Erzsébet Mernyák Mihály Szécsi Gyula Schneider |
| author_facet | Bianka Edina Herman Anita Kiss János Wölfling Erzsébet Mernyák Mihály Szécsi Gyula Schneider |
| author_sort | Bianka Edina Herman |
| collection | DOAJ |
| description | 17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) is a key enzyme in the biosynthesis of 17β-estradiol. Novel estrone-based compounds bearing various 15β-oxa-linked substituents and hydroxy, methoxy, benzyloxy, and sulfamate groups in position C3 as potential 17β-HSD1 inhibitors have been synthesized. In addition, in vitro inhibitory potentials measured in the presence of excess amount of NADPH or NADH were investigated. We observed substantial inhibitory potentials for several derivatives (IC50 < 1 µM) and increased binding affinities compared to unsubstituted core molecules. Binding and inhibition were found to be cofactor-dependent for some of the compounds and we propose structural explanations for this phenomenon. Our results may contribute to the development of new 17β-HSD1 inhibitors, potential drug candidates for antiestrogen therapy of hormone-dependent gynecological cancers. |
| first_indexed | 2024-12-11T14:50:01Z |
| format | Article |
| id | doaj.art-49ae5fd56767462fac654a3d6d2548dc |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2024-12-11T14:50:01Z |
| publishDate | 2019-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-49ae5fd56767462fac654a3d6d2548dc2022-12-22T01:01:30ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742019-01-013411271128610.1080/14756366.2019.16340641634064Synthesis of substituted 15β-alkoxy estrone derivatives and their cofactor-dependent inhibitory effect on 17β-HSD1Bianka Edina Herman0Anita Kiss1János Wölfling2Erzsébet Mernyák3Mihály Szécsi4Gyula Schneider5University of SzegedUniversity of SzegedUniversity of SzegedUniversity of SzegedUniversity of SzegedUniversity of Szeged17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) is a key enzyme in the biosynthesis of 17β-estradiol. Novel estrone-based compounds bearing various 15β-oxa-linked substituents and hydroxy, methoxy, benzyloxy, and sulfamate groups in position C3 as potential 17β-HSD1 inhibitors have been synthesized. In addition, in vitro inhibitory potentials measured in the presence of excess amount of NADPH or NADH were investigated. We observed substantial inhibitory potentials for several derivatives (IC50 < 1 µM) and increased binding affinities compared to unsubstituted core molecules. Binding and inhibition were found to be cofactor-dependent for some of the compounds and we propose structural explanations for this phenomenon. Our results may contribute to the development of new 17β-HSD1 inhibitors, potential drug candidates for antiestrogen therapy of hormone-dependent gynecological cancers.http://dx.doi.org/10.1080/14756366.2019.1634064michael additionsubstituted 15β-alkoxy-estrone derivatives17β-hsd1estrogen biosynthesisnadph and nadh |
| spellingShingle | Bianka Edina Herman Anita Kiss János Wölfling Erzsébet Mernyák Mihály Szécsi Gyula Schneider Synthesis of substituted 15β-alkoxy estrone derivatives and their cofactor-dependent inhibitory effect on 17β-HSD1 Journal of Enzyme Inhibition and Medicinal Chemistry michael addition substituted 15β-alkoxy-estrone derivatives 17β-hsd1 estrogen biosynthesis nadph and nadh |
| title | Synthesis of substituted 15β-alkoxy estrone derivatives and their cofactor-dependent inhibitory effect on 17β-HSD1 |
| title_full | Synthesis of substituted 15β-alkoxy estrone derivatives and their cofactor-dependent inhibitory effect on 17β-HSD1 |
| title_fullStr | Synthesis of substituted 15β-alkoxy estrone derivatives and their cofactor-dependent inhibitory effect on 17β-HSD1 |
| title_full_unstemmed | Synthesis of substituted 15β-alkoxy estrone derivatives and their cofactor-dependent inhibitory effect on 17β-HSD1 |
| title_short | Synthesis of substituted 15β-alkoxy estrone derivatives and their cofactor-dependent inhibitory effect on 17β-HSD1 |
| title_sort | synthesis of substituted 15β alkoxy estrone derivatives and their cofactor dependent inhibitory effect on 17β hsd1 |
| topic | michael addition substituted 15β-alkoxy-estrone derivatives 17β-hsd1 estrogen biosynthesis nadph and nadh |
| url | http://dx.doi.org/10.1080/14756366.2019.1634064 |
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