Synthesis of a new 2-prenylated quinoline as potential drug for metabolic syndrome with pan-PPAR activity and anti-inflammatory effects

Autores
Villarroel Vicente, Carlos; García, Ainhoa; Zibar, Khamis; Schiel, María Ayelén; Ferri, Jordi; Hennuyer, Nathalie; Enriz, Ricardo Daniel; Staels, Bart; Cortes, Diego; Cabedo, Nuria
Año de publicación
2024
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
We have previously reported the total synthesis and structure–activity relationships (SAR) of 2-prenylated benzopyrans with PPAR agonist activity. Herein, we have described the synthesis and PPAR activity of 2-prenylated benzopyrans and 2-prenylated quinolines. The benzopyran nucleus was generated via enamine-catalyzed Kabbe condensation, and the quinoline nucleus via Friedländer condensation. Results demonstrated that both benzopyran (5a) and quinoline (4b) derivatives bearing a γ,δ-unsaturated ester displayed a pan-PPAR agonism. They were full PPARα agonists, but showed different preferences for PPARγ and PPARβ/δ activation. It was noteworthy that quinoline 4b displayed full hPPARα activation (2-fold than WY-14,643), weak PPARβ/δ and partial PPARγ activation. In addition, quinoline 4b showed anti-inflammatory effects on macrophages by reducing LPS-induced expression of both MCP-1 and IL-6. Therefore, 4b emerges as a first-in-class promising hit compound for the development of potential therapeutics aimed at treating metabolic syndrome, metabolic dysfunction-associated fatty liver disease (MAFLD), and its associated cardiovascular comorbidities.
Fil: Villarroel Vicente, Carlos. Universidad de Valencia; España
Fil: García, Ainhoa. Universidad de Valencia; España
Fil: Zibar, Khamis. Universidad de Valencia; España
Fil: Schiel, María Ayelén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Fil: Ferri, Jordi. Universidad de Valencia; España
Fil: Hennuyer, Nathalie. Universidad de Valencia; España
Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Fil: Staels, Bart. Universidad de Valencia; España
Fil: Cortes, Diego. Universidad de Valencia; España
Fil: Cabedo, Nuria. Universidad de Valencia; España
Materia
PPAR Metabolic syndromeMAFLD2-
Prenylated benzopyrans2-Prenylated quinolines
Anti-inflammatory agents
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/265454
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/265454
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Synthesis of a new 2-prenylated quinoline as potential drug for metabolic syndrome with pan-PPAR activity and anti-inflammatory effectsVillarroel Vicente, CarlosGarcía, AinhoaZibar, KhamisSchiel, María AyelénFerri, JordiHennuyer, NathalieEnriz, Ricardo DanielStaels, BartCortes, DiegoCabedo, NuriaPPAR Metabolic syndromeMAFLD2-Prenylated benzopyrans2-Prenylated quinolinesAnti-inflammatory agentshttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1We have previously reported the total synthesis and structure–activity relationships (SAR) of 2-prenylated benzopyrans with PPAR agonist activity. Herein, we have described the synthesis and PPAR activity of 2-prenylated benzopyrans and 2-prenylated quinolines. The benzopyran nucleus was generated via enamine-catalyzed Kabbe condensation, and the quinoline nucleus via Friedländer condensation. Results demonstrated that both benzopyran (5a) and quinoline (4b) derivatives bearing a γ,δ-unsaturated ester displayed a pan-PPAR agonism. They were full PPARα agonists, but showed different preferences for PPARγ and PPARβ/δ activation. It was noteworthy that quinoline 4b displayed full hPPARα activation (2-fold than WY-14,643), weak PPARβ/δ and partial PPARγ activation. In addition, quinoline 4b showed anti-inflammatory effects on macrophages by reducing LPS-induced expression of both MCP-1 and IL-6. Therefore, 4b emerges as a first-in-class promising hit compound for the development of potential therapeutics aimed at treating metabolic syndrome, metabolic dysfunction-associated fatty liver disease (MAFLD), and its associated cardiovascular comorbidities.Fil: Villarroel Vicente, Carlos. Universidad de Valencia; EspañaFil: García, Ainhoa. Universidad de Valencia; EspañaFil: Zibar, Khamis. Universidad de Valencia; EspañaFil: Schiel, María Ayelén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Ferri, Jordi. Universidad de Valencia; EspañaFil: Hennuyer, Nathalie. Universidad de Valencia; EspañaFil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Staels, Bart. Universidad de Valencia; EspañaFil: Cortes, Diego. Universidad de Valencia; EspañaFil: Cabedo, Nuria. Universidad de Valencia; EspañaElsevier2024-07info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/265454Villarroel Vicente, Carlos; García, Ainhoa; Zibar, Khamis; Schiel, María Ayelén; Ferri, Jordi; et al.; Synthesis of a new 2-prenylated quinoline as potential drug for metabolic syndrome with pan-PPAR activity and anti-inflammatory effects; Elsevier; Biorganic and Medicinal Chemistry Letters; 106; 7-2024; 1-70960-894XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://linkinghub.elsevier.com/retrieve/pii/S0960894X24001720info:eu-repo/semantics/altIdentifier/doi/10.1016/j.bmcl.2024.129770info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-10T13:18:06Zoai:ri.conicet.gov.ar:11336/265454instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-10 13:18:06.857CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Synthesis of a new 2-prenylated quinoline as potential drug for metabolic syndrome with pan-PPAR activity and anti-inflammatory effects
title Synthesis of a new 2-prenylated quinoline as potential drug for metabolic syndrome with pan-PPAR activity and anti-inflammatory effects
spellingShingle Synthesis of a new 2-prenylated quinoline as potential drug for metabolic syndrome with pan-PPAR activity and anti-inflammatory effects
Villarroel Vicente, Carlos
PPAR Metabolic syndromeMAFLD2-
Prenylated benzopyrans2-Prenylated quinolines
Anti-inflammatory agents
title_short Synthesis of a new 2-prenylated quinoline as potential drug for metabolic syndrome with pan-PPAR activity and anti-inflammatory effects
title_full Synthesis of a new 2-prenylated quinoline as potential drug for metabolic syndrome with pan-PPAR activity and anti-inflammatory effects
title_fullStr Synthesis of a new 2-prenylated quinoline as potential drug for metabolic syndrome with pan-PPAR activity and anti-inflammatory effects
title_full_unstemmed Synthesis of a new 2-prenylated quinoline as potential drug for metabolic syndrome with pan-PPAR activity and anti-inflammatory effects
title_sort Synthesis of a new 2-prenylated quinoline as potential drug for metabolic syndrome with pan-PPAR activity and anti-inflammatory effects
dc.creator.none.fl_str_mv Villarroel Vicente, Carlos
García, Ainhoa
Zibar, Khamis
Schiel, María Ayelén
Ferri, Jordi
Hennuyer, Nathalie
Enriz, Ricardo Daniel
Staels, Bart
Cortes, Diego
Cabedo, Nuria
author Villarroel Vicente, Carlos
author_facet Villarroel Vicente, Carlos
García, Ainhoa
Zibar, Khamis
Schiel, María Ayelén
Ferri, Jordi
Hennuyer, Nathalie
Enriz, Ricardo Daniel
Staels, Bart
Cortes, Diego
Cabedo, Nuria
author_role author
author2 García, Ainhoa
Zibar, Khamis
Schiel, María Ayelén
Ferri, Jordi
Hennuyer, Nathalie
Enriz, Ricardo Daniel
Staels, Bart
Cortes, Diego
Cabedo, Nuria
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv PPAR Metabolic syndromeMAFLD2-
Prenylated benzopyrans2-Prenylated quinolines
Anti-inflammatory agents
topic PPAR Metabolic syndromeMAFLD2-
Prenylated benzopyrans2-Prenylated quinolines
Anti-inflammatory agents
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv We have previously reported the total synthesis and structure–activity relationships (SAR) of 2-prenylated benzopyrans with PPAR agonist activity. Herein, we have described the synthesis and PPAR activity of 2-prenylated benzopyrans and 2-prenylated quinolines. The benzopyran nucleus was generated via enamine-catalyzed Kabbe condensation, and the quinoline nucleus via Friedländer condensation. Results demonstrated that both benzopyran (5a) and quinoline (4b) derivatives bearing a γ,δ-unsaturated ester displayed a pan-PPAR agonism. They were full PPARα agonists, but showed different preferences for PPARγ and PPARβ/δ activation. It was noteworthy that quinoline 4b displayed full hPPARα activation (2-fold than WY-14,643), weak PPARβ/δ and partial PPARγ activation. In addition, quinoline 4b showed anti-inflammatory effects on macrophages by reducing LPS-induced expression of both MCP-1 and IL-6. Therefore, 4b emerges as a first-in-class promising hit compound for the development of potential therapeutics aimed at treating metabolic syndrome, metabolic dysfunction-associated fatty liver disease (MAFLD), and its associated cardiovascular comorbidities.
Fil: Villarroel Vicente, Carlos. Universidad de Valencia; España
Fil: García, Ainhoa. Universidad de Valencia; España
Fil: Zibar, Khamis. Universidad de Valencia; España
Fil: Schiel, María Ayelén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Fil: Ferri, Jordi. Universidad de Valencia; España
Fil: Hennuyer, Nathalie. Universidad de Valencia; España
Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Fil: Staels, Bart. Universidad de Valencia; España
Fil: Cortes, Diego. Universidad de Valencia; España
Fil: Cabedo, Nuria. Universidad de Valencia; España
description We have previously reported the total synthesis and structure–activity relationships (SAR) of 2-prenylated benzopyrans with PPAR agonist activity. Herein, we have described the synthesis and PPAR activity of 2-prenylated benzopyrans and 2-prenylated quinolines. The benzopyran nucleus was generated via enamine-catalyzed Kabbe condensation, and the quinoline nucleus via Friedländer condensation. Results demonstrated that both benzopyran (5a) and quinoline (4b) derivatives bearing a γ,δ-unsaturated ester displayed a pan-PPAR agonism. They were full PPARα agonists, but showed different preferences for PPARγ and PPARβ/δ activation. It was noteworthy that quinoline 4b displayed full hPPARα activation (2-fold than WY-14,643), weak PPARβ/δ and partial PPARγ activation. In addition, quinoline 4b showed anti-inflammatory effects on macrophages by reducing LPS-induced expression of both MCP-1 and IL-6. Therefore, 4b emerges as a first-in-class promising hit compound for the development of potential therapeutics aimed at treating metabolic syndrome, metabolic dysfunction-associated fatty liver disease (MAFLD), and its associated cardiovascular comorbidities.
publishDate 2024
dc.date.none.fl_str_mv 2024-07
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/265454
Villarroel Vicente, Carlos; García, Ainhoa; Zibar, Khamis; Schiel, María Ayelén; Ferri, Jordi; et al.; Synthesis of a new 2-prenylated quinoline as potential drug for metabolic syndrome with pan-PPAR activity and anti-inflammatory effects; Elsevier; Biorganic and Medicinal Chemistry Letters; 106; 7-2024; 1-7
0960-894X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/265454
identifier_str_mv Villarroel Vicente, Carlos; García, Ainhoa; Zibar, Khamis; Schiel, María Ayelén; Ferri, Jordi; et al.; Synthesis of a new 2-prenylated quinoline as potential drug for metabolic syndrome with pan-PPAR activity and anti-inflammatory effects; Elsevier; Biorganic and Medicinal Chemistry Letters; 106; 7-2024; 1-7
0960-894X
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://linkinghub.elsevier.com/retrieve/pii/S0960894X24001720
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.bmcl.2024.129770
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.993085

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