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Novel Disulfiram Derivatives as ALDH1a1-Selective Inhibitors

Aldehyde dehydrogenase-1a1 (ALDH1a1), the enzyme responsible for the oxidation of retinal into retinoic acid, represents a key therapeutic target for the treatment of debilitating disorders such as cancer, obesity, and inflammation. Drugs that can inhibit ALDH1a1 include disulfiram, an FDA-approved...

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Autor principal: Omran, Ziad
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8778300/
https://www.ncbi.nlm.nih.gov/pubmed/35056791
http://dx.doi.org/10.3390/molecules27020480
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author Omran, Ziad
author_facet Omran, Ziad
author_sort Omran, Ziad
collection PubMed
description Aldehyde dehydrogenase-1a1 (ALDH1a1), the enzyme responsible for the oxidation of retinal into retinoic acid, represents a key therapeutic target for the treatment of debilitating disorders such as cancer, obesity, and inflammation. Drugs that can inhibit ALDH1a1 include disulfiram, an FDA-approved drug to treat chronic alcoholism. Disulfiram, by carbamylation of the catalytic cysteines, irreversibly inhibits ALDH1a1 and ALDH2. The latter is the isozyme responsible for important physiological processes such as the second stage of alcohol metabolism. Given the fact that ALDH1a1 has a larger substrate tunnel than that in ALDH2, replacing disulfiram ethyl groups with larger motifs will yield selective ALDH1a1 inhibitors. We report herein the synthesis of new inhibitors of ALDH1a1 where (hetero)aromatic rings were introduced into the structure of disulfiram. Most of the developed compounds retained the anti-ALDH1a1 activity of disulfiram; however, they were completely devoid of inhibitory activity against ALDH2.
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spelling pubmed-87783002022-01-22 Novel Disulfiram Derivatives as ALDH1a1-Selective Inhibitors Omran, Ziad Molecules Article Aldehyde dehydrogenase-1a1 (ALDH1a1), the enzyme responsible for the oxidation of retinal into retinoic acid, represents a key therapeutic target for the treatment of debilitating disorders such as cancer, obesity, and inflammation. Drugs that can inhibit ALDH1a1 include disulfiram, an FDA-approved drug to treat chronic alcoholism. Disulfiram, by carbamylation of the catalytic cysteines, irreversibly inhibits ALDH1a1 and ALDH2. The latter is the isozyme responsible for important physiological processes such as the second stage of alcohol metabolism. Given the fact that ALDH1a1 has a larger substrate tunnel than that in ALDH2, replacing disulfiram ethyl groups with larger motifs will yield selective ALDH1a1 inhibitors. We report herein the synthesis of new inhibitors of ALDH1a1 where (hetero)aromatic rings were introduced into the structure of disulfiram. Most of the developed compounds retained the anti-ALDH1a1 activity of disulfiram; however, they were completely devoid of inhibitory activity against ALDH2. MDPI 2022-01-12 /pmc/articles/PMC8778300/ /pubmed/35056791 http://dx.doi.org/10.3390/molecules27020480 Text en © 2022 by the author. 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
Omran, Ziad
Novel Disulfiram Derivatives as ALDH1a1-Selective Inhibitors
title Novel Disulfiram Derivatives as ALDH1a1-Selective Inhibitors
title_full Novel Disulfiram Derivatives as ALDH1a1-Selective Inhibitors
title_fullStr Novel Disulfiram Derivatives as ALDH1a1-Selective Inhibitors
title_full_unstemmed Novel Disulfiram Derivatives as ALDH1a1-Selective Inhibitors
title_short Novel Disulfiram Derivatives as ALDH1a1-Selective Inhibitors
title_sort novel disulfiram derivatives as aldh1a1-selective inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8778300/
https://www.ncbi.nlm.nih.gov/pubmed/35056791
http://dx.doi.org/10.3390/molecules27020480
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