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Bisavenathramide Analogues as Nrf2 Inductors and Neuroprotectors in In Vitro Models of Oxidative Stress and Hyperphosphorylation
Oxidative stress is crucial to the outbreak and advancement of neurodegenerative diseases and is a common factor to many of them. We describe the synthesis of a library of derivatives of the 4-arylmethylen-2-pyrrolin-5-one framework by sequential application of a three-component reaction of primary...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230565/ https://www.ncbi.nlm.nih.gov/pubmed/34200859 http://dx.doi.org/10.3390/antiox10060941 |
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author | Cores, Ángel Abril, Sheila Michalska, Patrycja Duarte, Pablo Olives, Ana I. Martín, M. Antonia Villacampa, Mercedes León, Rafael Menéndez, J. Carlos |
author_facet | Cores, Ángel Abril, Sheila Michalska, Patrycja Duarte, Pablo Olives, Ana I. Martín, M. Antonia Villacampa, Mercedes León, Rafael Menéndez, J. Carlos |
author_sort | Cores, Ángel |
collection | PubMed |
description | Oxidative stress is crucial to the outbreak and advancement of neurodegenerative diseases and is a common factor to many of them. We describe the synthesis of a library of derivatives of the 4-arylmethylen-2-pyrrolin-5-one framework by sequential application of a three-component reaction of primary amines, β-dicarbonyl compounds, and α-haloketones and a Knoevenagel condensation. These compounds can be viewed as cyclic amides of caffeic and ferulic acids, and are also structurally related to the bisavenanthramide family of natural antioxidants. Most members of the library showed low cytotoxicity and good activity as inductors of Nrf2, a transcription factor that acts as the master regulator of the antioxidant response associated with activation of the antioxidant response element (ARE). Nrf2-dependent protein expression was also proved by the significant increase in the levels of the HMOX1 and NQO1 proteins. Some compounds exerted neuroprotective properties in oxidative stress situations, such as rotenone/oligomycin-induced toxicity, and also against protein hyperphosphorylation induced by the phosphatase inhibitor okadaic acid. Compound 3i, which can be considered a good candidate for further hit-to-lead development against neurodegenerative diseases due to its well-balanced multitarget profile, was further characterized by proving its ability to reduce phosphorylated Tau levels. |
format | Online Article Text |
id | pubmed-8230565 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-82305652021-06-26 Bisavenathramide Analogues as Nrf2 Inductors and Neuroprotectors in In Vitro Models of Oxidative Stress and Hyperphosphorylation Cores, Ángel Abril, Sheila Michalska, Patrycja Duarte, Pablo Olives, Ana I. Martín, M. Antonia Villacampa, Mercedes León, Rafael Menéndez, J. Carlos Antioxidants (Basel) Article Oxidative stress is crucial to the outbreak and advancement of neurodegenerative diseases and is a common factor to many of them. We describe the synthesis of a library of derivatives of the 4-arylmethylen-2-pyrrolin-5-one framework by sequential application of a three-component reaction of primary amines, β-dicarbonyl compounds, and α-haloketones and a Knoevenagel condensation. These compounds can be viewed as cyclic amides of caffeic and ferulic acids, and are also structurally related to the bisavenanthramide family of natural antioxidants. Most members of the library showed low cytotoxicity and good activity as inductors of Nrf2, a transcription factor that acts as the master regulator of the antioxidant response associated with activation of the antioxidant response element (ARE). Nrf2-dependent protein expression was also proved by the significant increase in the levels of the HMOX1 and NQO1 proteins. Some compounds exerted neuroprotective properties in oxidative stress situations, such as rotenone/oligomycin-induced toxicity, and also against protein hyperphosphorylation induced by the phosphatase inhibitor okadaic acid. Compound 3i, which can be considered a good candidate for further hit-to-lead development against neurodegenerative diseases due to its well-balanced multitarget profile, was further characterized by proving its ability to reduce phosphorylated Tau levels. MDPI 2021-06-10 /pmc/articles/PMC8230565/ /pubmed/34200859 http://dx.doi.org/10.3390/antiox10060941 Text en © 2021 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 Cores, Ángel Abril, Sheila Michalska, Patrycja Duarte, Pablo Olives, Ana I. Martín, M. Antonia Villacampa, Mercedes León, Rafael Menéndez, J. Carlos Bisavenathramide Analogues as Nrf2 Inductors and Neuroprotectors in In Vitro Models of Oxidative Stress and Hyperphosphorylation |
title | Bisavenathramide Analogues as Nrf2 Inductors and Neuroprotectors in In Vitro Models of Oxidative Stress and Hyperphosphorylation |
title_full | Bisavenathramide Analogues as Nrf2 Inductors and Neuroprotectors in In Vitro Models of Oxidative Stress and Hyperphosphorylation |
title_fullStr | Bisavenathramide Analogues as Nrf2 Inductors and Neuroprotectors in In Vitro Models of Oxidative Stress and Hyperphosphorylation |
title_full_unstemmed | Bisavenathramide Analogues as Nrf2 Inductors and Neuroprotectors in In Vitro Models of Oxidative Stress and Hyperphosphorylation |
title_short | Bisavenathramide Analogues as Nrf2 Inductors and Neuroprotectors in In Vitro Models of Oxidative Stress and Hyperphosphorylation |
title_sort | bisavenathramide analogues as nrf2 inductors and neuroprotectors in in vitro models of oxidative stress and hyperphosphorylation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230565/ https://www.ncbi.nlm.nih.gov/pubmed/34200859 http://dx.doi.org/10.3390/antiox10060941 |
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