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

Abstract : 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.
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https://hal-normandie-univ.archives-ouvertes.fr/hal-02173275
Contributor : Madeleine Roux-Merlin <>
Submitted on : Thursday, July 4, 2019 - 1:45:59 PM
Last modification on : Saturday, September 19, 2020 - 3:47:47 AM

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Almudena Bermejo, Aida Collado, Isabel Barrachina, Patrice Marqués, Noureddine El Aouad, et al.. Polycerasoidol, a Natural Prenylated Benzopyran with a Dual PPARα/PPARγ Agonist Activity and Anti-inflammatory Effect. Journal of Natural Products, American Chemical Society, 2019, 82 (7), pp.1733-2066. ⟨10.1021/acs.jnatprod.9b00003⟩. ⟨hal-02173275⟩

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