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    Nitrone-Trolox conjugate as an inhibitor of lipid oxidation: Towards synergistic antioxidant effects

    Year: 2019

    Journal: Biochim. Biophys. Acta-Biomembr., Volume 1861, 1-Aug, page 1489–1501

    Authors: Socrier, Larissa; Rosselin, Marie; Giraldoa, Ana Milena Gomez; Chantemargu, Benjamin; Di Meo, Florent; Trouillas, Patrick; Durand, Gregory; Morandat, Sandrine

    Organizations: French "Ministere de l'enseignement superieur de la recherche et de l'innovation"; "Provence Alpes Cote d'Azur" regional councilRegion Provence-Alpes-Cote d'Azur; Centre National de la Recherche Scientifique (CNRS)Centre National de la Recherche Scientifique (CNRS); Universite de Technologie de Compiegne; Universite d'Avignon et des Pays du Vaucluse; Czech Science FoundationGrant Agency of the Czech Republic [P208/12/G016]; National Program of Sustainability from the Ministry of Youth, Education and Sports of the Czech Republic [L01305]

    Keywords: Model membranes; Lipid oxidation; Amphiphilic nitrone; Trolox; Antioxidant; Synergism

    Free radical scavengers like a-phenyl-N-tert-butylnitrone (PBN) and 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox) have been widely used as protective agents in various biomimetic and biological models. A series of three amphiphilic Trolox and PBN derivatives have been designed by adding to those molecules a perfluorinated chain as well as a sugar group in order to render them amphiphilic. In this work, we have studied the interactions between these derivatives and lipid membranes to understand how they influence their ability to prevent membrane lipid oxidation. We showed the derivatives better inhibited the AAPH-induced oxidation of 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLiPC) small unilamellar vesicles (SUVs) than the parent compounds. One of the derivatives, bearing both PBN and Trolox moieties on the same fluorinated carrier, exhibited a synergistic antioxidant effect by delaying the oxidation process. We next investigated the ability of the derivatives to interact with DLiPC membranes in order to better understand the differences observed regarding the antioxidant properties. Surface tension and fluorescence spectroscopy experiments revealed the derivatives exhibited the ability to form monolayers at the air/water interface and spontaneously penetrated lipid membranes, underlying pronounced hydrophobic properties in comparison to the parent compounds. We observed a correlation between the hydrophobic properties, the depth of penetration and the antioxidant properties and showed that the location of these derivatives in the membrane is a key parameter to rationalize their antioxidant efficiency. Molecular dynamics (MD) simulations supported the understanding of the mechanism of action, highlighting various key physical-chemical descriptors.
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