Development of 2- and 3-prenylated quinolines and tetrahydroquinolines with PPAR activity: From hit to lead and a novel pan-PPAR agonist as a potential candidate for metabolic synd...

Autores
Villarroel Vicente, Carlos; Martínez Solsona, María; García, Ainhoa; Vila, Laura; Zibar, Khamis; Schiel, María Ayelén; Hennuyer, Nathalie; Clarisse, Dorien; Enriz, Ricardo Daniel; Staels, Bart; De Bosscher, Karolien; González Navarro, Herminia; Cortes, Diego; Cabedo, Nuria
Año de publicación
2025
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Peroxisome proliferator-activated receptors (PPARs) represent highly valuable therapeutic targets for the treatment of type 2 diabetes (T2D) and hypertriglyceridemia, both closely linked to the development of metabolic syndrome (MetS). Herein, we have synthesised two series of prenylated quinolines either at the 2- or 3-position, and their tetrahydroquinolines (THQs) using the Friedländer cyclodehydration, followed by the Grignard reaction and subsequent Johnson-Claisen rearrangement. All the synthesised compounds were evaluated in vitro for activity at each of the human PPAR, their cytotoxicity, their capacity to activate the PPAR target gene PDK4 and their anti-inflammatory effects. The compounds with a seven‑carbon prenylated side chain at the 2-position, such as THQ 5a and 6a (series a), displayed similar pan-PPAR agonism to the 2-prenylated benzopyran analogue BP-2. The compounds with a six‑carbon prenylated side chain at the 3-position, such as 5b and 6b (series b), had stronger selectivity for PPARα activation. The luciferase assays of the PPRE-driven gene PDK4 showed that THQ 5a, 5b, and quinoline 8a increased the transactivation of the PDK4-Luc + reporter, which confirmed their potential capacity to promote lipid metabolism. THQs 5a, 5b, and quinoline 8b repressed the transactivation of the TNFα-dependent NF-κB-Luc + reporter and efficiently down-regulated the transcription of several TNFα-induced pro-inflammatory genes. Furthermore, THQ 5a improves total cholesterol, non-HDL-c, HOMA-IR index and lipid metabolism in ob/ob mice, without increasing liver enzymes. Our results suggest that THQ 5a is a promising lead compound in the development of agents for treating metabolic disorders (T2D and dyslipidaemias), which may prevent further cardiovascular comorbidities associated with MetS.
Fil: Villarroel Vicente, Carlos. Universidad de Valencia; España
Fil: Martínez Solsona, María. Universidad de Valencia; España
Fil: García, Ainhoa. Universidad de Valencia; España
Fil: Vila, Laura. Universidad de Valencia; España
Fil: Zibar, Khamis. Institut Pasteur de Paris.; Francia
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: Hennuyer, Nathalie. Institut Pasteur de Paris.; Francia
Fil: Clarisse, Dorien. University of Ghent; Bélgica
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. Institut Pasteur de Paris.; Francia
Fil: De Bosscher, Karolien. University of Ghent; Bélgica
Fil: González Navarro, Herminia. Universidad de Valencia; España
Fil: Cortes, Diego. Universidad de Valencia; España
Fil: Cabedo, Nuria. Universidad de Valencia; España
Materia
PPAR
MEDICINAL CHEMISTRY
MOLECULAR DYNAMICS
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/289971
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/289971
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repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Development of 2- and 3-prenylated quinolines and tetrahydroquinolines with PPAR activity: From hit to lead and a novel pan-PPAR agonist as a potential candidate for metabolic syndromeVillarroel Vicente, CarlosMartínez Solsona, MaríaGarcía, AinhoaVila, LauraZibar, KhamisSchiel, María AyelénHennuyer, NathalieClarisse, DorienEnriz, Ricardo DanielStaels, BartDe Bosscher, KarolienGonzález Navarro, HerminiaCortes, DiegoCabedo, NuriaPPARMEDICINAL CHEMISTRYMOLECULAR DYNAMICShttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1Peroxisome proliferator-activated receptors (PPARs) represent highly valuable therapeutic targets for the treatment of type 2 diabetes (T2D) and hypertriglyceridemia, both closely linked to the development of metabolic syndrome (MetS). Herein, we have synthesised two series of prenylated quinolines either at the 2- or 3-position, and their tetrahydroquinolines (THQs) using the Friedländer cyclodehydration, followed by the Grignard reaction and subsequent Johnson-Claisen rearrangement. All the synthesised compounds were evaluated in vitro for activity at each of the human PPAR, their cytotoxicity, their capacity to activate the PPAR target gene PDK4 and their anti-inflammatory effects. The compounds with a seven‑carbon prenylated side chain at the 2-position, such as THQ 5a and 6a (series a), displayed similar pan-PPAR agonism to the 2-prenylated benzopyran analogue BP-2. The compounds with a six‑carbon prenylated side chain at the 3-position, such as 5b and 6b (series b), had stronger selectivity for PPARα activation. The luciferase assays of the PPRE-driven gene PDK4 showed that THQ 5a, 5b, and quinoline 8a increased the transactivation of the PDK4-Luc + reporter, which confirmed their potential capacity to promote lipid metabolism. THQs 5a, 5b, and quinoline 8b repressed the transactivation of the TNFα-dependent NF-κB-Luc + reporter and efficiently down-regulated the transcription of several TNFα-induced pro-inflammatory genes. Furthermore, THQ 5a improves total cholesterol, non-HDL-c, HOMA-IR index and lipid metabolism in ob/ob mice, without increasing liver enzymes. Our results suggest that THQ 5a is a promising lead compound in the development of agents for treating metabolic disorders (T2D and dyslipidaemias), which may prevent further cardiovascular comorbidities associated with MetS.Fil: Villarroel Vicente, Carlos. Universidad de Valencia; EspañaFil: Martínez Solsona, María. Universidad de Valencia; EspañaFil: García, Ainhoa. Universidad de Valencia; EspañaFil: Vila, Laura. Universidad de Valencia; EspañaFil: Zibar, Khamis. Institut Pasteur de Paris.; FranciaFil: 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: Hennuyer, Nathalie. Institut Pasteur de Paris.; FranciaFil: Clarisse, Dorien. University of Ghent; BélgicaFil: 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. Institut Pasteur de Paris.; FranciaFil: De Bosscher, Karolien. University of Ghent; BélgicaFil: González Navarro, Herminia. Universidad de Valencia; EspañaFil: Cortes, Diego. Universidad de Valencia; EspañaFil: Cabedo, Nuria. Universidad de Valencia; EspañaAcademic Press Inc Elsevier Science2025-06-15info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/289971Villarroel Vicente, Carlos; Martínez Solsona, María; García, Ainhoa; Vila, Laura; Zibar, Khamis; et al.; Development of 2- and 3-prenylated quinolines and tetrahydroquinolines with PPAR activity: From hit to lead and a novel pan-PPAR agonist as a potential candidate for metabolic syndrome; Academic Press Inc Elsevier Science; Bioorganic Chemistry; 160; 15-6-2025; 1-140045-2068CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/journal/bioorganic-chemistry/vol/160/suppl/Cinfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.bioorg.2025.108450info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-08-25T14:48:10Zoai:ri.conicet.gov.ar:11336/289971instacron: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:34982026-08-25 14:48:10.908CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Development of 2- and 3-prenylated quinolines and tetrahydroquinolines with PPAR activity: From hit to lead and a novel pan-PPAR agonist as a potential candidate for metabolic syndrome
title Development of 2- and 3-prenylated quinolines and tetrahydroquinolines with PPAR activity: From hit to lead and a novel pan-PPAR agonist as a potential candidate for metabolic syndrome
spellingShingle Development of 2- and 3-prenylated quinolines and tetrahydroquinolines with PPAR activity: From hit to lead and a novel pan-PPAR agonist as a potential candidate for metabolic syndrome
Villarroel Vicente, Carlos
PPAR
MEDICINAL CHEMISTRY
MOLECULAR DYNAMICS
title_short Development of 2- and 3-prenylated quinolines and tetrahydroquinolines with PPAR activity: From hit to lead and a novel pan-PPAR agonist as a potential candidate for metabolic syndrome
title_full Development of 2- and 3-prenylated quinolines and tetrahydroquinolines with PPAR activity: From hit to lead and a novel pan-PPAR agonist as a potential candidate for metabolic syndrome
title_fullStr Development of 2- and 3-prenylated quinolines and tetrahydroquinolines with PPAR activity: From hit to lead and a novel pan-PPAR agonist as a potential candidate for metabolic syndrome
title_full_unstemmed Development of 2- and 3-prenylated quinolines and tetrahydroquinolines with PPAR activity: From hit to lead and a novel pan-PPAR agonist as a potential candidate for metabolic syndrome
title_sort Development of 2- and 3-prenylated quinolines and tetrahydroquinolines with PPAR activity: From hit to lead and a novel pan-PPAR agonist as a potential candidate for metabolic syndrome
dc.creator.none.fl_str_mv Villarroel Vicente, Carlos
Martínez Solsona, María
García, Ainhoa
Vila, Laura
Zibar, Khamis
Schiel, María Ayelén
Hennuyer, Nathalie
Clarisse, Dorien
Enriz, Ricardo Daniel
Staels, Bart
De Bosscher, Karolien
González Navarro, Herminia
Cortes, Diego
Cabedo, Nuria
author Villarroel Vicente, Carlos
author_facet Villarroel Vicente, Carlos
Martínez Solsona, María
García, Ainhoa
Vila, Laura
Zibar, Khamis
Schiel, María Ayelén
Hennuyer, Nathalie
Clarisse, Dorien
Enriz, Ricardo Daniel
Staels, Bart
De Bosscher, Karolien
González Navarro, Herminia
Cortes, Diego
Cabedo, Nuria
author_role author
author2 Martínez Solsona, María
García, Ainhoa
Vila, Laura
Zibar, Khamis
Schiel, María Ayelén
Hennuyer, Nathalie
Clarisse, Dorien
Enriz, Ricardo Daniel
Staels, Bart
De Bosscher, Karolien
González Navarro, Herminia
Cortes, Diego
Cabedo, Nuria
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv PPAR
MEDICINAL CHEMISTRY
MOLECULAR DYNAMICS
topic PPAR
MEDICINAL CHEMISTRY
MOLECULAR DYNAMICS
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Peroxisome proliferator-activated receptors (PPARs) represent highly valuable therapeutic targets for the treatment of type 2 diabetes (T2D) and hypertriglyceridemia, both closely linked to the development of metabolic syndrome (MetS). Herein, we have synthesised two series of prenylated quinolines either at the 2- or 3-position, and their tetrahydroquinolines (THQs) using the Friedländer cyclodehydration, followed by the Grignard reaction and subsequent Johnson-Claisen rearrangement. All the synthesised compounds were evaluated in vitro for activity at each of the human PPAR, their cytotoxicity, their capacity to activate the PPAR target gene PDK4 and their anti-inflammatory effects. The compounds with a seven‑carbon prenylated side chain at the 2-position, such as THQ 5a and 6a (series a), displayed similar pan-PPAR agonism to the 2-prenylated benzopyran analogue BP-2. The compounds with a six‑carbon prenylated side chain at the 3-position, such as 5b and 6b (series b), had stronger selectivity for PPARα activation. The luciferase assays of the PPRE-driven gene PDK4 showed that THQ 5a, 5b, and quinoline 8a increased the transactivation of the PDK4-Luc + reporter, which confirmed their potential capacity to promote lipid metabolism. THQs 5a, 5b, and quinoline 8b repressed the transactivation of the TNFα-dependent NF-κB-Luc + reporter and efficiently down-regulated the transcription of several TNFα-induced pro-inflammatory genes. Furthermore, THQ 5a improves total cholesterol, non-HDL-c, HOMA-IR index and lipid metabolism in ob/ob mice, without increasing liver enzymes. Our results suggest that THQ 5a is a promising lead compound in the development of agents for treating metabolic disorders (T2D and dyslipidaemias), which may prevent further cardiovascular comorbidities associated with MetS.
Fil: Villarroel Vicente, Carlos. Universidad de Valencia; España
Fil: Martínez Solsona, María. Universidad de Valencia; España
Fil: García, Ainhoa. Universidad de Valencia; España
Fil: Vila, Laura. Universidad de Valencia; España
Fil: Zibar, Khamis. Institut Pasteur de Paris.; Francia
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: Hennuyer, Nathalie. Institut Pasteur de Paris.; Francia
Fil: Clarisse, Dorien. University of Ghent; Bélgica
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. Institut Pasteur de Paris.; Francia
Fil: De Bosscher, Karolien. University of Ghent; Bélgica
Fil: González Navarro, Herminia. Universidad de Valencia; España
Fil: Cortes, Diego. Universidad de Valencia; España
Fil: Cabedo, Nuria. Universidad de Valencia; España
description Peroxisome proliferator-activated receptors (PPARs) represent highly valuable therapeutic targets for the treatment of type 2 diabetes (T2D) and hypertriglyceridemia, both closely linked to the development of metabolic syndrome (MetS). Herein, we have synthesised two series of prenylated quinolines either at the 2- or 3-position, and their tetrahydroquinolines (THQs) using the Friedländer cyclodehydration, followed by the Grignard reaction and subsequent Johnson-Claisen rearrangement. All the synthesised compounds were evaluated in vitro for activity at each of the human PPAR, their cytotoxicity, their capacity to activate the PPAR target gene PDK4 and their anti-inflammatory effects. The compounds with a seven‑carbon prenylated side chain at the 2-position, such as THQ 5a and 6a (series a), displayed similar pan-PPAR agonism to the 2-prenylated benzopyran analogue BP-2. The compounds with a six‑carbon prenylated side chain at the 3-position, such as 5b and 6b (series b), had stronger selectivity for PPARα activation. The luciferase assays of the PPRE-driven gene PDK4 showed that THQ 5a, 5b, and quinoline 8a increased the transactivation of the PDK4-Luc + reporter, which confirmed their potential capacity to promote lipid metabolism. THQs 5a, 5b, and quinoline 8b repressed the transactivation of the TNFα-dependent NF-κB-Luc + reporter and efficiently down-regulated the transcription of several TNFα-induced pro-inflammatory genes. Furthermore, THQ 5a improves total cholesterol, non-HDL-c, HOMA-IR index and lipid metabolism in ob/ob mice, without increasing liver enzymes. Our results suggest that THQ 5a is a promising lead compound in the development of agents for treating metabolic disorders (T2D and dyslipidaemias), which may prevent further cardiovascular comorbidities associated with MetS.
publishDate 2025
dc.date.none.fl_str_mv 2025-06-15
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/11336/289971
Villarroel Vicente, Carlos; Martínez Solsona, María; García, Ainhoa; Vila, Laura; Zibar, Khamis; et al.; Development of 2- and 3-prenylated quinolines and tetrahydroquinolines with PPAR activity: From hit to lead and a novel pan-PPAR agonist as a potential candidate for metabolic syndrome; Academic Press Inc Elsevier Science; Bioorganic Chemistry; 160; 15-6-2025; 1-14
0045-2068
CONICET Digital
CONICET
url http://hdl.handle.net/11336/289971
identifier_str_mv Villarroel Vicente, Carlos; Martínez Solsona, María; García, Ainhoa; Vila, Laura; Zibar, Khamis; et al.; Development of 2- and 3-prenylated quinolines and tetrahydroquinolines with PPAR activity: From hit to lead and a novel pan-PPAR agonist as a potential candidate for metabolic syndrome; Academic Press Inc Elsevier Science; Bioorganic Chemistry; 160; 15-6-2025; 1-14
0045-2068
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://www.sciencedirect.com/journal/bioorganic-chemistry/vol/160/suppl/C
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.bioorg.2025.108450
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Academic Press Inc Elsevier Science
publisher.none.fl_str_mv Academic Press Inc Elsevier Science
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 13.24418

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