Synthesis, Biological Evaluation and Docking Studies of 13-Epimeric 10-fluoro- and 10-Chloroestra-1,4-dien-3-ones as Potential Aromatase Inhibitors
Fluorination of 13-epimeric estrones and their 17-deoxy counterparts was performed with Selectfluor as the reagent. In acetonitrile or trifluoroacetic acid (TFA), 10β-fluoroestra-1,4-dien-3-ones were formed exclusively. Mechanistic investigations suggest that fluorinations occurred via SET...
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MDPI AG
2019-05-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/24/9/1783 |
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| author | Rebeka Jójárt Péter Traj Édua Kovács Ágnes Horváth Gyula Schneider Mihály Szécsi Attila Pál Gábor Paragi Erzsébet Mernyák |
| author_facet | Rebeka Jójárt Péter Traj Édua Kovács Ágnes Horváth Gyula Schneider Mihály Szécsi Attila Pál Gábor Paragi Erzsébet Mernyák |
| author_sort | Rebeka Jójárt |
| collection | DOAJ |
| description | Fluorination of 13-epimeric estrones and their 17-deoxy counterparts was performed with Selectfluor as the reagent. In acetonitrile or trifluoroacetic acid (TFA), 10β-fluoroestra-1,4-dien-3-ones were formed exclusively. Mechanistic investigations suggest that fluorinations occurred via SET in acetonitrile, but another mechanism was operative in TFA. Simultaneous application of N-chlorosuccinimide (NCS) and Selectfluor in TFA led to a 1.3:1 mixture of 10β-fluoroestra-1,4-dien-3-one and 10β-chloroestra-1,4-dien-3-one as the main products. The potential inhibitory action of the 10-fluoro- or 10-chloroestra-1,4-dien-3-one products on human aromatase was investigated via in vitro radiosubstrate incubation. The classical estrane conformation with <i>trans</i> ring anellations and a 13β-methyl group seems to be crucial for the inhibition of the enzyme, while test compounds bearing the 13β-methyl group exclusively displayed potent inhibitory action with submicromolar or micromolar IC<sub>50</sub> values. Concerning molecular level explanation of biological activity or inactivity, computational simulations were performed. Docking studies reinforced that besides the well-known Met374 H-bond connection, the stereocenter in the 13 position has an important role in the binding affinity. The configuration inversion at C-13 results in weaker binding of 13α-estrone derivatives to the aromatase enzyme. |
| first_indexed | 2024-12-10T09:23:54Z |
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| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-10T09:23:54Z |
| publishDate | 2019-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-87d9d2e1fda9488b82298defd5fa72852022-12-22T01:54:36ZengMDPI AGMolecules1420-30492019-05-01249178310.3390/molecules24091783molecules24091783Synthesis, Biological Evaluation and Docking Studies of 13-Epimeric 10-fluoro- and 10-Chloroestra-1,4-dien-3-ones as Potential Aromatase InhibitorsRebeka Jójárt0Péter Traj1Édua Kovács2Ágnes Horváth3Gyula Schneider4Mihály Szécsi5Attila Pál6Gábor Paragi7Erzsébet Mernyák8Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, HungaryDepartment of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, HungaryDepartment of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, HungaryDepartment of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, HungaryDepartment of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary1st Department of Medicine, University of Szeged, Korányi fasor 8–10, H-6720 Szeged, HungaryDepartment of Medicinal Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, HungaryMTA-SZTE Biomimetic Systems Research Group, University of Szeged, Dóm tér 8, H-6720 Szeged, HungaryDepartment of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, HungaryFluorination of 13-epimeric estrones and their 17-deoxy counterparts was performed with Selectfluor as the reagent. In acetonitrile or trifluoroacetic acid (TFA), 10β-fluoroestra-1,4-dien-3-ones were formed exclusively. Mechanistic investigations suggest that fluorinations occurred via SET in acetonitrile, but another mechanism was operative in TFA. Simultaneous application of N-chlorosuccinimide (NCS) and Selectfluor in TFA led to a 1.3:1 mixture of 10β-fluoroestra-1,4-dien-3-one and 10β-chloroestra-1,4-dien-3-one as the main products. The potential inhibitory action of the 10-fluoro- or 10-chloroestra-1,4-dien-3-one products on human aromatase was investigated via in vitro radiosubstrate incubation. The classical estrane conformation with <i>trans</i> ring anellations and a 13β-methyl group seems to be crucial for the inhibition of the enzyme, while test compounds bearing the 13β-methyl group exclusively displayed potent inhibitory action with submicromolar or micromolar IC<sub>50</sub> values. Concerning molecular level explanation of biological activity or inactivity, computational simulations were performed. Docking studies reinforced that besides the well-known Met374 H-bond connection, the stereocenter in the 13 position has an important role in the binding affinity. The configuration inversion at C-13 results in weaker binding of 13α-estrone derivatives to the aromatase enzyme.https://www.mdpi.com/1420-3049/24/9/178313α-estroneSelectfluoraromatasedockingTEMPOsingle electron transfer |
| spellingShingle | Rebeka Jójárt Péter Traj Édua Kovács Ágnes Horváth Gyula Schneider Mihály Szécsi Attila Pál Gábor Paragi Erzsébet Mernyák Synthesis, Biological Evaluation and Docking Studies of 13-Epimeric 10-fluoro- and 10-Chloroestra-1,4-dien-3-ones as Potential Aromatase Inhibitors Molecules 13α-estrone Selectfluor aromatase docking TEMPO single electron transfer |
| title | Synthesis, Biological Evaluation and Docking Studies of 13-Epimeric 10-fluoro- and 10-Chloroestra-1,4-dien-3-ones as Potential Aromatase Inhibitors |
| title_full | Synthesis, Biological Evaluation and Docking Studies of 13-Epimeric 10-fluoro- and 10-Chloroestra-1,4-dien-3-ones as Potential Aromatase Inhibitors |
| title_fullStr | Synthesis, Biological Evaluation and Docking Studies of 13-Epimeric 10-fluoro- and 10-Chloroestra-1,4-dien-3-ones as Potential Aromatase Inhibitors |
| title_full_unstemmed | Synthesis, Biological Evaluation and Docking Studies of 13-Epimeric 10-fluoro- and 10-Chloroestra-1,4-dien-3-ones as Potential Aromatase Inhibitors |
| title_short | Synthesis, Biological Evaluation and Docking Studies of 13-Epimeric 10-fluoro- and 10-Chloroestra-1,4-dien-3-ones as Potential Aromatase Inhibitors |
| title_sort | synthesis biological evaluation and docking studies of 13 epimeric 10 fluoro and 10 chloroestra 1 4 dien 3 ones as potential aromatase inhibitors |
| topic | 13α-estrone Selectfluor aromatase docking TEMPO single electron transfer |
| url | https://www.mdpi.com/1420-3049/24/9/1783 |
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