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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doaj-87d9d2e1fda9488b82298defd5fa72852020-11-25T01:36:38ZengMDPI 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 |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Rebeka Jójárt Péter Traj Édua Kovács Ágnes Horváth Gyula Schneider Mihály Szécsi Attila Pál Gábor Paragi Erzsébet Mernyák |
| 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 |
| author_facet |
Rebeka Jójárt Péter Traj Édua Kovács Ágnes Horváth Gyula Schneider Mihály Szécsi Attila Pál Gábor Paragi Erzsébet Mernyák |
| author_sort |
Rebeka Jójárt |
| 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_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_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_sort |
synthesis, biological evaluation and docking studies of 13-epimeric 10-fluoro- and 10-chloroestra-1,4-dien-3-ones as potential aromatase inhibitors |
| publisher |
MDPI AG |
| series |
Molecules |
| issn |
1420-3049 |
| publishDate |
2019-05-01 |
| 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. |
| topic |
13α-estrone Selectfluor aromatase docking TEMPO single electron transfer |
| url |
https://www.mdpi.com/1420-3049/24/9/1783 |
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