A Novel Nitrone-Trolox Conjugate Inhibits Membrane Lipid Oxidation Through Synergistic Antioxidant Effects

Abstract

Polyunsaturated fatty acids are particularly sensitive to the deleterious effects of reactive oxygen species (ROS) as ROS can trigger their degradation through a chemical reaction called lipid peroxidation. Lipid oxidation has been reported to be involved in the early stages of several diseases as well as the deterioration of food supplies. To prevent the deleterious effects of ROS, water soluble 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. In order to increase the hydrophobicity and the ability of these compounds to interact with membranes, three amphiphilic Trolox and PBN derivatives were recently designed by adding a perfluorinated chain to Trolox and PBN. A sugar moiety was added as well to ensure water solubility. In the present work, we studied the physical-chemical properties of the derivatives and related their antioxidant properties to their ability to interact with lipid membranes. We first investigated their ability to inhibit the AAPH-induced oxidation of 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC) liposomes as well as their ability to interact with DLPC membranes. Results evidenced that the three derivatives are efficient to prevent lipid oxidation and that the location in the hydrophobic core of the membrane is a key parameter in the antioxidant efficiency. The derivative bearing both PBN and Trolox moieties on the same fluorinated carrier exhibited a synergistic antioxidant effect by delaying the oxidation process and by scavenging free radicals. Molecular dynamics simulations supported the understanding of the mechanism of action, highlighting various key physical-chemical descriptors.