Free radical scavengers like α-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.

INSERM Univ Limoges IPPRITT U1248 Faculty of Pharmacy 2 rue du Dr Marcland 87025 Limoges France

Institut des Biomolécules Max Mousseron and Avignon University Equipe Chimie Bioorganique et Systèmes Amphiphiles 301 rue Baruch de Spinoza F 84916 Avignon Cedex 9 France

RCPTM Palacký University Faculty of Sciences Šlechtitelů 27 78371 Olomouc Czech Republic

Sorbonne Universités Université de technologie de Compiègne CNRS Génie Enzymatique et Cellulaire FRE 3580 Centre de recherches Royallieu CS 60319 60203 Compiègne cedex France

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