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Multitarget Hybrid Fasudil Derivatives as a New Approach to the Potential Treatment of Amyotrophic Lateral Sclerosis
[Image: see text] Hybrid compounds containing structural fragments of the Rho kinase inhibitor fasudil and the NRF2 inducers caffeic and ferulic acids were designed with the aid of docking and molecular mechanics studies. Following the synthesis of the compounds using a peptide-coupling methodology,...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9132363/ https://www.ncbi.nlm.nih.gov/pubmed/34985276 http://dx.doi.org/10.1021/acs.jmedchem.1c01255 |
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author | Martín-Cámara, Olmo Arribas, Marina Wells, Geoffrey Morales-Tenorio, Marcos Martín-Requero, Ángeles Porras, Gracia Martínez, Ana Giorgi, Giorgio López-Alvarado, Pilar Lastres-Becker, Isabel Menéndez, J. Carlos |
author_facet | Martín-Cámara, Olmo Arribas, Marina Wells, Geoffrey Morales-Tenorio, Marcos Martín-Requero, Ángeles Porras, Gracia Martínez, Ana Giorgi, Giorgio López-Alvarado, Pilar Lastres-Becker, Isabel Menéndez, J. Carlos |
author_sort | Martín-Cámara, Olmo |
collection | PubMed |
description | [Image: see text] Hybrid compounds containing structural fragments of the Rho kinase inhibitor fasudil and the NRF2 inducers caffeic and ferulic acids were designed with the aid of docking and molecular mechanics studies. Following the synthesis of the compounds using a peptide-coupling methodology, they were characterized for their ROCK2 inhibition, radical scavenging, effects on cell viability (MTT assay), and NRF2 induction (luciferase assay). One of the compounds (1d) was selected in view of its good multitarget profile and good tolerability. It was able to induce the NRF2 signature, promoting the expression of the antioxidant response enzymes HO-1 and NQO1, via a KEAP1-dependent mechanism. Analysis of mRNA and protein levels of the NRF2 pathway showed that 1d induced the NRF2 signature in control and SOD1-ALS lymphoblasts but not in sALS, where it was already increased in the basal state. These results show the therapeutic potential of this compound, especially for ALS patients with a SOD1 mutation. |
format | Online Article Text |
id | pubmed-9132363 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-91323632022-05-26 Multitarget Hybrid Fasudil Derivatives as a New Approach to the Potential Treatment of Amyotrophic Lateral Sclerosis Martín-Cámara, Olmo Arribas, Marina Wells, Geoffrey Morales-Tenorio, Marcos Martín-Requero, Ángeles Porras, Gracia Martínez, Ana Giorgi, Giorgio López-Alvarado, Pilar Lastres-Becker, Isabel Menéndez, J. Carlos J Med Chem [Image: see text] Hybrid compounds containing structural fragments of the Rho kinase inhibitor fasudil and the NRF2 inducers caffeic and ferulic acids were designed with the aid of docking and molecular mechanics studies. Following the synthesis of the compounds using a peptide-coupling methodology, they were characterized for their ROCK2 inhibition, radical scavenging, effects on cell viability (MTT assay), and NRF2 induction (luciferase assay). One of the compounds (1d) was selected in view of its good multitarget profile and good tolerability. It was able to induce the NRF2 signature, promoting the expression of the antioxidant response enzymes HO-1 and NQO1, via a KEAP1-dependent mechanism. Analysis of mRNA and protein levels of the NRF2 pathway showed that 1d induced the NRF2 signature in control and SOD1-ALS lymphoblasts but not in sALS, where it was already increased in the basal state. These results show the therapeutic potential of this compound, especially for ALS patients with a SOD1 mutation. American Chemical Society 2022-01-05 2022-02-10 /pmc/articles/PMC9132363/ /pubmed/34985276 http://dx.doi.org/10.1021/acs.jmedchem.1c01255 Text en © 2022 American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Martín-Cámara, Olmo Arribas, Marina Wells, Geoffrey Morales-Tenorio, Marcos Martín-Requero, Ángeles Porras, Gracia Martínez, Ana Giorgi, Giorgio López-Alvarado, Pilar Lastres-Becker, Isabel Menéndez, J. Carlos Multitarget Hybrid Fasudil Derivatives as a New Approach to the Potential Treatment of Amyotrophic Lateral Sclerosis |
title | Multitarget Hybrid
Fasudil Derivatives as a New Approach
to the Potential Treatment of Amyotrophic Lateral Sclerosis |
title_full | Multitarget Hybrid
Fasudil Derivatives as a New Approach
to the Potential Treatment of Amyotrophic Lateral Sclerosis |
title_fullStr | Multitarget Hybrid
Fasudil Derivatives as a New Approach
to the Potential Treatment of Amyotrophic Lateral Sclerosis |
title_full_unstemmed | Multitarget Hybrid
Fasudil Derivatives as a New Approach
to the Potential Treatment of Amyotrophic Lateral Sclerosis |
title_short | Multitarget Hybrid
Fasudil Derivatives as a New Approach
to the Potential Treatment of Amyotrophic Lateral Sclerosis |
title_sort | multitarget hybrid
fasudil derivatives as a new approach
to the potential treatment of amyotrophic lateral sclerosis |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9132363/ https://www.ncbi.nlm.nih.gov/pubmed/34985276 http://dx.doi.org/10.1021/acs.jmedchem.1c01255 |
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