Divalent Amino-Acid-Based Amphiphilic Antioxidants: Synthesis, Self-Assembling Properties, and Biological Evaluation

We report herein the synthesis of a divalent amphiphilic carrier onto which α-phenyl-N-tert-butyl nitrone (PBN) and 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox) antioxidants were grafted to give the divalent derivative called FATxPBN. The divalent carrier consists of two lysine amino acids as a scaffold upon which the antioxidant moieties are grafted, a perfluorinated chain that supplies hydrophobicity, and a sugar-based polar headgroup that ensures water solubility. For the sake of comparison, a divalent PBN derivative called FADiPBN was also synthesized. The self-aggregation properties of FATxPBN and FADiPBN were studied by means of surface tension, dynamic light scattering, and transmission electron microscopy methods, and showed they form small micelles (i.e., 12 and 6 nm diameter, respectively) at submillimolar concentrations (i.e., 0.01 and 0.05 mM, respectively), in agreement with partition coefficient values. The superior antioxidant properties of FATxPBN over FADiPBN and the parent compounds PBN and Trolox were demonstrated using in vitro ABTS(•+) reduction (98%) and soybean lipoxygenase inhibition (94%) assays. Finally, FATxPBN was found to significantly inhibit hyperglycemia-induced toxicity on an ex-vivo rat model, demonstrating its potency as a bioactive antioxidant against oxidative stress-induced damage.