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

1Free radical scavengers like -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 the parent molecules both a perfluorinated chain and a sugar group in order to render them amphiphilic. In this work, we have studied the interaction of these derivatives with lipid membranes and how it correlates to their antioxidant properties.\n\nThe three derivatives form monolayers at the air/water interface. We next investigated the ability of each derivative to interact with 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC) as well as their efficiency to inhibit the AAPH-induced oxidation of DLPC liposomes. The location of these derivatives in the membrane is a key parameter to rationalize their antioxidant efficiency. The derivative bearing both the PBN and the Trolox antioxidant moieties on the same fluorinated carrier exhibited a synergistic antioxidant effect by delaying the oxidation process. Molecular dynamics (MD) simulations supported the understanding of the mechanism of action, highlighting various key physical-chemical descriptors.\n\nGraphical abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=82 SRC=\"FIGDIR/small/323386_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (20K):\norg.highwire.dtl.DTLVardef@15e2ce5org.highwire.dtl.DTLVardef@1d58ee3org.highwire.dtl.DTLVardef@197f9d2org.highwire.dtl.DTLVardef@9279ff_HPS_FORMAT_FIGEXP M_FIG C_FIG Highlights- Amphiphilic fluorinated antioxidants efficiently inhibit lipid oxidation\n- The perfluorinated chain allows the insertion into membranes\n- The nature of the antioxidant is a key parameter in the antioxidant efficiency\n- The combination of Trolox and PBN results in a synergistic antioxidant effect\n\n\nCondensed running titleTrolox derivatives limit lipid oxidation