Chemical Synthesis and Biological Evaluation of 3-Substituted Estrone/Estradiol Derivatives as 17β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors Acting via a Reverse Orientation of the Natural Substrate Estrone
Estradiol (E2) plays an important role in the progression of diseases such as breast cancer and endometriosis. Inhibition of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), the enzyme that catalyzes the last step in the biosynthesis of the estrogenic hormone E2, therefore constitutes an interest...
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MDPI AG
2023-01-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/2/632 |
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| author | Adrien Djiemeny Ngueta Jenny Roy René Maltais Donald Poirier |
| author_facet | Adrien Djiemeny Ngueta Jenny Roy René Maltais Donald Poirier |
| author_sort | Adrien Djiemeny Ngueta |
| collection | DOAJ |
| description | Estradiol (E2) plays an important role in the progression of diseases such as breast cancer and endometriosis. Inhibition of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), the enzyme that catalyzes the last step in the biosynthesis of the estrogenic hormone E2, therefore constitutes an interesting approach for the treatment of these two estrogen-dependent diseases. In order to obtain new inhibitors of 17β-HSD1, the impact of a <i>m</i>-carbamoylphenyloxy group at position three of an estrane nucleus was evaluated by preparing three derivatives of estrone (E1) and E2 using a microwave-assisted synthesis of diaryl ethers. Their inhibitory activity was addressed on two cell lines (T-47D and Z-12) representative of breast cancer and endometriosis, respectively, but unlike T-47D cells, Z-12 cells were not found suitable for testing potential 17β-HSD1 inhibitors. Thus, the addition of the <i>m</i>-carbamoylphenyl group at C3 of E1 (compound <b>5</b>) did not increase the inhibition of E1 to E2 transformation by 17β-HSD1 present in T-47D cells (IC<sub>50</sub> = 0.31 and 0.21 μM for <b>5</b> and E1, respectively), and this negative effect was more obvious for E2 derivatives <b>6</b> and <b>10</b> (IC<sub>50</sub> = 1.2 and 1.3 μM, respectively). Molecular docking allowed us to identify key interactions with 17β-HSD1 and to highlight these new inhibitors’ actions through an opposite orientation than natural enzyme substrate E1′s classical one. Furthermore, molecular modeling experiments explain the better inhibitory activity of E1-ether derivative <b>5,</b> as opposed to the E2-ether derivatives <b>6</b> and <b>10</b>. Finally, when tested on T-47D and Z-12 cells, compounds <b>5</b>, <b>6</b> and <b>10</b> did not stimulate the proliferation of these two estrogen-dependent cell lines. In fact, they reduced it. |
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| language | English |
| last_indexed | 2024-03-09T11:35:54Z |
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| spelling | doaj.art-699c84e7e18441a2aac9be8d60c9a6212023-11-30T23:42:35ZengMDPI AGMolecules1420-30492023-01-0128263210.3390/molecules28020632Chemical Synthesis and Biological Evaluation of 3-Substituted Estrone/Estradiol Derivatives as 17β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors Acting via a Reverse Orientation of the Natural Substrate EstroneAdrien Djiemeny Ngueta0Jenny Roy1René Maltais2Donald Poirier3Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec Research Center—Université Laval, Quebec, QC G1V 4G2, CanadaLaboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec Research Center—Université Laval, Quebec, QC G1V 4G2, CanadaLaboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec Research Center—Université Laval, Quebec, QC G1V 4G2, CanadaLaboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec Research Center—Université Laval, Quebec, QC G1V 4G2, CanadaEstradiol (E2) plays an important role in the progression of diseases such as breast cancer and endometriosis. Inhibition of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), the enzyme that catalyzes the last step in the biosynthesis of the estrogenic hormone E2, therefore constitutes an interesting approach for the treatment of these two estrogen-dependent diseases. In order to obtain new inhibitors of 17β-HSD1, the impact of a <i>m</i>-carbamoylphenyloxy group at position three of an estrane nucleus was evaluated by preparing three derivatives of estrone (E1) and E2 using a microwave-assisted synthesis of diaryl ethers. Their inhibitory activity was addressed on two cell lines (T-47D and Z-12) representative of breast cancer and endometriosis, respectively, but unlike T-47D cells, Z-12 cells were not found suitable for testing potential 17β-HSD1 inhibitors. Thus, the addition of the <i>m</i>-carbamoylphenyl group at C3 of E1 (compound <b>5</b>) did not increase the inhibition of E1 to E2 transformation by 17β-HSD1 present in T-47D cells (IC<sub>50</sub> = 0.31 and 0.21 μM for <b>5</b> and E1, respectively), and this negative effect was more obvious for E2 derivatives <b>6</b> and <b>10</b> (IC<sub>50</sub> = 1.2 and 1.3 μM, respectively). Molecular docking allowed us to identify key interactions with 17β-HSD1 and to highlight these new inhibitors’ actions through an opposite orientation than natural enzyme substrate E1′s classical one. Furthermore, molecular modeling experiments explain the better inhibitory activity of E1-ether derivative <b>5,</b> as opposed to the E2-ether derivatives <b>6</b> and <b>10</b>. Finally, when tested on T-47D and Z-12 cells, compounds <b>5</b>, <b>6</b> and <b>10</b> did not stimulate the proliferation of these two estrogen-dependent cell lines. In fact, they reduced it.https://www.mdpi.com/1420-3049/28/2/632steroidchemical synthesisinhibitor17β-HSD1estrogen |
| spellingShingle | Adrien Djiemeny Ngueta Jenny Roy René Maltais Donald Poirier Chemical Synthesis and Biological Evaluation of 3-Substituted Estrone/Estradiol Derivatives as 17β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors Acting via a Reverse Orientation of the Natural Substrate Estrone Molecules steroid chemical synthesis inhibitor 17β-HSD1 estrogen |
| title | Chemical Synthesis and Biological Evaluation of 3-Substituted Estrone/Estradiol Derivatives as 17β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors Acting via a Reverse Orientation of the Natural Substrate Estrone |
| title_full | Chemical Synthesis and Biological Evaluation of 3-Substituted Estrone/Estradiol Derivatives as 17β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors Acting via a Reverse Orientation of the Natural Substrate Estrone |
| title_fullStr | Chemical Synthesis and Biological Evaluation of 3-Substituted Estrone/Estradiol Derivatives as 17β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors Acting via a Reverse Orientation of the Natural Substrate Estrone |
| title_full_unstemmed | Chemical Synthesis and Biological Evaluation of 3-Substituted Estrone/Estradiol Derivatives as 17β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors Acting via a Reverse Orientation of the Natural Substrate Estrone |
| title_short | Chemical Synthesis and Biological Evaluation of 3-Substituted Estrone/Estradiol Derivatives as 17β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors Acting via a Reverse Orientation of the Natural Substrate Estrone |
| title_sort | chemical synthesis and biological evaluation of 3 substituted estrone estradiol derivatives as 17β hydroxysteroid dehydrogenase type 1 inhibitors acting via a reverse orientation of the natural substrate estrone |
| topic | steroid chemical synthesis inhibitor 17β-HSD1 estrogen |
| url | https://www.mdpi.com/1420-3049/28/2/632 |
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