6533b855fe1ef96bd12b128d

RESEARCH PRODUCT

Polycerasoidol, a Natural Prenylated Benzopyran with a Dual PPARα/PPARγ Agonist Activity and Anti-inflammatory Effect

Bruno FigadèreAida ColladoPatrice MarquesIsabel BarrachinaDiego CortesFrancisco Matías GaribottoMaria-jesus SanzNuria CabedoLaura PiquerasDaniel Henri CaignardXavier FranckAlmudena BermejoNoureddine El AouadRicardo D. EnrizFernando D. SuvireCatherine Dacquet

subject

Anti-Inflammatory AgentsRXRα/PPARγPharmaceutical ScienceRetinoid X receptorPharmacology01 natural sciencesAnalytical ChemistryStructure-Activity Relationshipchemistry.chemical_compoundTransactivationPrenylationPOLYCERASOIDOLDrug DiscoveryHumansStructure–activity relationshipGlucose homeostasisBenzopyransPPAR alphaMOLECULAR MODELINGCytotoxicityPrenylationPharmacologyMolecular Structure010405 organic chemistryChemistry[CHIM.ORGA]Chemical Sciences/Organic chemistryOrganic ChemistryCiencias QuímicasNATARUL PRODUCTSPeroxisome0104 chemical sciencesBenzopyranPPAR gamma010404 medicinal & biomolecular chemistryQuímica OrgánicaComplementary and alternative medicineMolecular MedicineCIENCIAS NATURALES Y EXACTAS

description

Dual peroxisome proliferator-activated receptor-α/γ (PPARα/γ) agonists regulate both lipid and glucose homeostasis under different metabolic conditions and can exert anti-inflammatory activity. We investigated the potential dual PPARα/γ agonism of prenylated benzopyrans polycerasoidol (1) and polycerasoidin (2) and their derivatives for novel drug development. Nine semisynthetic derivatives were prepared from the natural polycerasoidol (1) and polycerasoidin (2), which were evaluated for PPARα, -γ, -δ and retinoid X receptor-α activity in transactivation assays. Polycerasoidol (1) exhibited potent dual PPARα/γ agonism and low cytotoxicity. Structure–activity relationship studies revealed that a free phenol group at C-6 and a carboxylic acid at C-9′ were key features for dual PPARα/γ agonism activity. Molecular modeling indicated the relevance of these groups for optimal ligand binding to the PPARα and PPARγ domains. In addition, polycerasoidol (1) exhibited a potent anti-inflammatory effect by inhibiting mononuclear leukocyte adhesion to the dysfunctional endothelium in a concentration-dependent manner via RXRα/PPARγ interactions. Therefore, polycerasoidol (1) can be considered a hit-to-lead molecule for the further development of novel dual PPARα/γ agonists capable of preventing cardiovascular events associated with metabolic disorders. Fil: Bermejo, Almudena. Universidad de Valencia; España Fil: Collado, Aida. Universidad de Valencia; España Fil: Barrachina, Isabel. Universidad de Valencia; España Fil: Marqués, Patrice. Universidad de Valencia; España Fil: El Aouad, Noureddine. Universidad de Valencia; España Fil: Franck, Xavier. Université de Rouen; Francia Fil: Garibotto, Francisco Matías. 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: Dacquet, Catherine. Institut de Recherches Servier; Francia Fil: Caignard, Daniel H.. Institut de Recherches Servier; Francia Fil: Suvire, Fernando Daniel. Universidad Nacional de San Luis; Argentina 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: Piqueras, Laura. Universidad de Valencia; España Fil: Figadère, Bruno. Université Paris Sud; Francia Fil: Sanz, María-Jesús. Universidad de Valencia; España Fil: Cabedo, Nuria. Universidad de Valencia; España Fil: Cortes, Diego. Universidad de Valencia; España

yearjournalcountryeditionlanguage
2019-07-03
10.1021/acs.jnatprod.9b00003https://hal-normandie-univ.archives-ouvertes.fr/hal-02173275