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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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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2022
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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. |
format | Online Article Text |
id | pubmed-8778300 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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