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

Abstract

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.

(Cryo)Transmission Electron Microscopy of Phospholipid Model Membranes Interacting with Amphiphilic and Polyphilic Molecules

“…TEM investigations using negatively stained samples of aqueous solutions of FATxPBN above the critical micellar concentration showed the formation of spherical micelles (Figure 5E,F) with a diameter range between ~6 and ~25 nm. In the TEM images, the micelles appear mostly ellipsoidal, and the average diameter determined by computer-assisted imaging analysis is ~16 ± 2 nm, which is in agreement with dynamic light scattering data [69]. However, TEM clearly demonstrated a large variety in shape and size of the formed micelles.…”

“…Amphiphilicity is also a key feature for bioactivity and protection against in vitro and in vivo oxidative toxicity, for example, light-induced retinal degeneration [70]. Rosselin et al [69] synthesized the amphiphilic divalent antioxidant FATxPBN (Figure 5D) consisting of two lysine amino acids as a scaffold upon which two antioxidant moieties are grafted. An additional perfluorinated chain supplies additional hydrophobicity without inducing a cytolytic effect [71].…”

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

“…30-40 µM). Trolox, FATxPBN, FATx and FAPBN present IC 50 (concentration required to half-reduce the oxidation in absence of antioxidant) values of 4.0, 0.6, 0.9, and 29.5 µM, respectively, no IC 50 was determined for PBN.The better lipid peroxidation inhibitor capacity of Trolox compare to PBN agrees with previous work, where we showed that Trolox was more efficient than PBN to scavenge ABTS +• radicals(22). All three fluorinated derivatives exhibit lower IC 50 than their parent derivatives.…”

“…In both cases, the authors demonstrated that compared to PBN, the derivatives presented an enhanced protective activity against stroke and retina light-induced damages, respectively. Along the same line, Trolox and PBN amphiphilic derivatives (21,22) have recently been synthesized. They are bearing, on one hand, a perfluorinated chain to increase hydrophobicity without inducing a cytolytic effect (23) and on the other hand, a sugar group to maintain water solubility ( Fig.…”

“…The nature of the free-radical scavenger moieties and their location in the membranes were analyzed as key parameters to rationalize the antioxidant activity of these derivatives, which was supported by molecular dynamics (MD) simulations. FATxPBN (22) were synthesized according to the procedure previously published.…”