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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,...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
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.
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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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