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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...

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Autores principales: Cores, Ángel, Abril, Sheila, Michalska, Patrycja, Duarte, Pablo, Olives, Ana I., Martín, M. Antonia, Villacampa, Mercedes, León, Rafael, Menéndez, J. Carlos
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
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.
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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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