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Chemistry Related to the Catalytic Cycle of the Antioxidant Ebselen

The antioxidant drug ebselen has been widely studied in both laboratories and in clinical trials. The catalytic mechanism by which it destroys hydrogen peroxide via reduction with glutathione or other thiols is complex and has been the subject of considerable debate. During reinvestigations of sever...

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Autores principales: Sands, Kai N., Burman, Austin L., Ansah-Asamoah, Esther, Back, Thomas G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10180093/
https://www.ncbi.nlm.nih.gov/pubmed/37175141
http://dx.doi.org/10.3390/molecules28093732
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author Sands, Kai N.
Burman, Austin L.
Ansah-Asamoah, Esther
Back, Thomas G.
author_facet Sands, Kai N.
Burman, Austin L.
Ansah-Asamoah, Esther
Back, Thomas G.
author_sort Sands, Kai N.
collection PubMed
description The antioxidant drug ebselen has been widely studied in both laboratories and in clinical trials. The catalytic mechanism by which it destroys hydrogen peroxide via reduction with glutathione or other thiols is complex and has been the subject of considerable debate. During reinvestigations of several key steps, we found that the seleninamide that comprises the first oxidation product of ebselen underwent facile reversible methanolysis to an unstable seleninate ester and two dimeric products. In its reaction with benzyl alcohol, the seleninamide produced a benzyl ester that reacted readily by selenoxide elimination, with formation of benzaldehyde. Oxidation of ebselen seleninic acid did not afford a selenonium seleninate salt as previously observed with benzene seleninic acid, but instead generated a mixture of the seleninic and selenonic acids. Thiolysis of ebselen with benzyl thiol was faster than oxidation by ca. an order of magnitude and produced a stable selenenyl sulfide. When glutathione was employed, the product rapidly disproportionated to glutathione disulfide and ebselen diselenide. Oxidation of the S-benzyl selenenyl sulfide, or thiolysis of the seleninamide with benzyl thiol, afforded a transient thiolseleninate that also readily underwent selenoxide elimination. The S-benzyl derivative disproportionated readily when catalyzed by the simultaneous presence of both the thiol and triethylamine. The phenylthio analogue disproportionated when exposed to ambient or UV (360 nm) light by a proposed radical mechanism. These observations provide additional insight into several reactions and intermediates related to ebselen.
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spelling pubmed-101800932023-05-13 Chemistry Related to the Catalytic Cycle of the Antioxidant Ebselen Sands, Kai N. Burman, Austin L. Ansah-Asamoah, Esther Back, Thomas G. Molecules Article The antioxidant drug ebselen has been widely studied in both laboratories and in clinical trials. The catalytic mechanism by which it destroys hydrogen peroxide via reduction with glutathione or other thiols is complex and has been the subject of considerable debate. During reinvestigations of several key steps, we found that the seleninamide that comprises the first oxidation product of ebselen underwent facile reversible methanolysis to an unstable seleninate ester and two dimeric products. In its reaction with benzyl alcohol, the seleninamide produced a benzyl ester that reacted readily by selenoxide elimination, with formation of benzaldehyde. Oxidation of ebselen seleninic acid did not afford a selenonium seleninate salt as previously observed with benzene seleninic acid, but instead generated a mixture of the seleninic and selenonic acids. Thiolysis of ebselen with benzyl thiol was faster than oxidation by ca. an order of magnitude and produced a stable selenenyl sulfide. When glutathione was employed, the product rapidly disproportionated to glutathione disulfide and ebselen diselenide. Oxidation of the S-benzyl selenenyl sulfide, or thiolysis of the seleninamide with benzyl thiol, afforded a transient thiolseleninate that also readily underwent selenoxide elimination. The S-benzyl derivative disproportionated readily when catalyzed by the simultaneous presence of both the thiol and triethylamine. The phenylthio analogue disproportionated when exposed to ambient or UV (360 nm) light by a proposed radical mechanism. These observations provide additional insight into several reactions and intermediates related to ebselen. MDPI 2023-04-26 /pmc/articles/PMC10180093/ /pubmed/37175141 http://dx.doi.org/10.3390/molecules28093732 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Sands, Kai N.
Burman, Austin L.
Ansah-Asamoah, Esther
Back, Thomas G.
Chemistry Related to the Catalytic Cycle of the Antioxidant Ebselen
title Chemistry Related to the Catalytic Cycle of the Antioxidant Ebselen
title_full Chemistry Related to the Catalytic Cycle of the Antioxidant Ebselen
title_fullStr Chemistry Related to the Catalytic Cycle of the Antioxidant Ebselen
title_full_unstemmed Chemistry Related to the Catalytic Cycle of the Antioxidant Ebselen
title_short Chemistry Related to the Catalytic Cycle of the Antioxidant Ebselen
title_sort chemistry related to the catalytic cycle of the antioxidant ebselen
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10180093/
https://www.ncbi.nlm.nih.gov/pubmed/37175141
http://dx.doi.org/10.3390/molecules28093732
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