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

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 v...

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Autores: Villarroel-Vicente, C, García, A, Zibar, K, Schiel, MA, Ferri, J, Hennuyer, N, Enriz, RD, Staels, B, Cortes, D, Cabedo, N
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:INCLIVA
Repositorio:r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
OAI Identifier:oai:incliva.fundanetsuite.com:p18412
Acceso en línea:https://incliva.portalinvestigacion.com/publicaciones/18412
Access Level:acceso abierto
Palabra clave:PPAR
Metabolic syndrome
MAFLD
2-Prenylated benzopyrans
2-Prenylated quinolines
Anti-inflammatory agents
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spelling Synthesis of a new 2-prenylated quinoline as potential drug for metabolic syndrome with pan-PPAR activity and anti-inflammatory effectsVillarroel-Vicente, CGarcía, AZibar, KSchiel, MAFerri, JHennuyer, NEnriz, RDStaels, BCortes, DCabedo, NPPARMetabolic syndromeMAFLD2-Prenylated benzopyrans2-Prenylated quinolinesAnti-inflammatory agentsWe 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 Friedla<spacing diaeresis>nder condensation. Results demonstrated that both benzopyran (5a) and quinoline (4b) derivatives bearing a gamma,8-unsaturated ester displayed a pan-PPAR agonism. They were full PPAR alpha agonists, but showed different preferences for PPAR gamma and PPARI3/8 activation. It was noteworthy that quinoline 4b displayed full hPPAR alpha activation (2-fold than WY-14,643), weak PPARI3/8 and partial PPAR gamma 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.PERGAMON-ELSEVIER SCIENCE LTD2024info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://incliva.portalinvestigacion.com/publicaciones/18412BIOORGANIC & MEDICINAL CHEMISTRY LETTERSISSN: 0960894XISSNe: 14643405reponame:r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVAinstname:INCLIVAInglésinfo:eu-repo/semantics/openAccessoai:incliva.fundanetsuite.com:p184122026-06-07T16:35:31Z
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, C
PPAR
Metabolic syndrome
MAFLD
2-Prenylated benzopyrans
2-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, C
García, A
Zibar, K
Schiel, MA
Ferri, J
Hennuyer, N
Enriz, RD
Staels, B
Cortes, D
Cabedo, N
author Villarroel-Vicente, C
author_facet Villarroel-Vicente, C
García, A
Zibar, K
Schiel, MA
Ferri, J
Hennuyer, N
Enriz, RD
Staels, B
Cortes, D
Cabedo, N
author_role author
author2 García, A
Zibar, K
Schiel, MA
Ferri, J
Hennuyer, N
Enriz, RD
Staels, B
Cortes, D
Cabedo, N
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv PPAR
Metabolic syndrome
MAFLD
2-Prenylated benzopyrans
2-Prenylated quinolines
Anti-inflammatory agents
topic PPAR
Metabolic syndrome
MAFLD
2-Prenylated benzopyrans
2-Prenylated quinolines
Anti-inflammatory agents
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 Friedla<spacing diaeresis>nder condensation. Results demonstrated that both benzopyran (5a) and quinoline (4b) derivatives bearing a gamma,8-unsaturated ester displayed a pan-PPAR agonism. They were full PPAR alpha agonists, but showed different preferences for PPAR gamma and PPARI3/8 activation. It was noteworthy that quinoline 4b displayed full hPPAR alpha activation (2-fold than WY-14,643), weak PPARI3/8 and partial PPAR gamma 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
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://incliva.portalinvestigacion.com/publicaciones/18412
url https://incliva.portalinvestigacion.com/publicaciones/18412
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv PERGAMON-ELSEVIER SCIENCE LTD
publisher.none.fl_str_mv PERGAMON-ELSEVIER SCIENCE LTD
dc.source.none.fl_str_mv BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
ISSN: 0960894X
ISSNe: 14643405
reponame:r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
instname:INCLIVA
instname_str INCLIVA
reponame_str r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
collection r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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