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

Fecha de publicación: 15/06/2025 Fecha Ahead of Print: 01/04/2025

Autores de INCLIVA

Ainhoa Natividad García Martín

Autor
Laura Vila Dasí

Autor
Herminia González Navarro

Autor
Diego Cortes Martinez

Autor
Nuria Cabedo Escrig

Autor

Participantes ajenos a INCLIVA

Villarroel-Vicente, C
Martínez-Solsona, M
Zibar, K
Schiel, MA
Hennuyer, N
Clarisse, D
Enriz, RD
Staels, B
De Bosscher, K

Grupos y Plataformas de I+D+i

Grupo de investigación en Enfermedades Metabólicas

Established Researcher

Herminia González Navarro
Grupo de investigación en Química Médica para el Desarrollo de Fármacos

Responsable de Plataforma

Nuria Cabedo Escrig
Unidad de Cromatografía Líquida Analítica

Responsable de Plataforma

Nuria Cabedo Escrig

Abstract

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 Friedla<spacing diaeresis>nder 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 PPAR<euro> 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 TNF<euro>-dependent NF-kappa B-Luc + reporter and efficiently down-regulated the transcription of several TNF<euro>-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.