• The Synthesis and Reactivity of Vitamin E Quinones

      Krueger, Nicholas W.; Centre for Biotechnology
      Vitamin E has been the subject of numerous studies over the last nine decades since its discovery. Still, the biological activity of vitamin E is not completely understood. Various studies suggest that the primary function of vitamin E is a fat-soluble antioxidant preventing lipid peroxidation in cellular membranes. The antioxidant efficiency across the vitamin E isomers have been shown to be similar in vitro in various organic solvents and aqueous lipid suspensions. Despite these results, significantly different biological effects have been observed in biological assays supplemented with the various tocols. Furthermore, the differences are more pronounced when comparing the biological effects of the α-tocols to non α-tocols. We hypothesized the different biological effects observed were correlated to differences in the chemical reactivity of the products of tocol oxidation: tocol quinones. Herein, an investigation of the adduct formation of tocol quinones with N-acetyl cysteine (NAC) is described. The synthesis of the tocopheryl quinones is described via the two-electron oxidation of the parent tocols with ceric ammonium nitrate supported on silica. The synthesis of α-tocopherol quinone and α-tocotrienol quinone produced the target compounds in 80% yield. The oxidations of the other tocol isoforms yielded para-tocol quinones (29-45% yield) and ortho-tocol quinones (20-35% yield). The rate of reaction of the tocopheryl quinones with NAC was monitored by following the production of the tocopherol hydroquinone adduct by the increase in absorption at 308 nm over time in a 67% methanol/ 33% aqueous Tris/HCl buffer. The curves generated were fit to a one-phase exponential. The rate of reaction increased as the pH increased for the γ- and δ-tocopheryl quinone isoforms. There was no reactivity observed between the α-tocopheryl quinone isoforms and NAC. There was no significant difference in the reactivity between the tocopherol quinones and tocotrienol quinones with the same methylation pattern. At the most physiologically relevant pH in our study (pH = 7.5), the δ-tocopheryl quinones (k ≈ 0.63) reacted approximately 8 times faster than the γ-tocopheryl quinones (k ≈ 0.08). The electrochemistry of the parent tocols was studied using cyclic voltammetry (CV). The formal redox potential increased slightly as the methylation on the chromanol ring decreased while no significant differences between the tocopherols and tocotrienols were established. The CV of all tocols showed two quasi-reversible one-electron oxidation processes; the first oxidation produced a radical cation, which quickly deprotonated to form a tocopheryl radical, which then undergoes a second oxidation to the corresponding phenoxonium cation. The redox activity of the tocopheryl quinones was also studied using CV. The quinones underwent a quasi-reversible two one-electron reduction process. The δ-tocopheryl quinones have the lowest formal redox potential which slightly increases as methylation increases, while there were no significant differences in the electrochemical behavior of the tocopheryl quinones and the tocotrienyl quinones with the same methylation. We have presented reaction rate differences in the reactivity of the tocol quinones which correlates to the differences in biological activity observed by others with respect to the methylation pattern on the chromanol ring, while no differences in the chemical reactivity of the tocopherol and tocotrienol quinones was observed. Still, this presents convincing evidence that the activity of the tocol quinones should be considered in biological assays.