A new insight into the oxidative mechanism of caffeine and related methylxanthines in aprotic medium: May caffeine be really considered as an antioxidant?

[object Object]Background: Antioxidant properties have been recently suggested for caffeine that seems showing protective effects against damages caused by oxidative stress. In particular, a HO% scavenging activity has been ascribed to caffeine. Even if the oxidation of caffeine has been widely studied, the antioxidant mechanism is still far to be understood. Methods: The electrochemical behavior of caffeine, theobromine and theophylline was studied in aprotic medium by cyclic voltammetry and electrolysis in UV-vis cell; a computational analysis of the molecular structures based on the Density Functional Theory was performed; the reactivity of all substrates towards lead dioxide, superoxide and galvinoxyl radical was followed by UV-vis spectrophotometry. Results: Results supported the mono-electronic oxidation of the C4]C5 bond for all substrates at high oxidation potentials, the electron-transfer process leading to a radical cation or a neutral radical according to the starting methylxanthine N7-substituted (caffeine and theobromine) or N7-unsubstituted (theophylline), respectively. A different following chemical fate might be predicted for the radical cation or the neutral radical. No interaction was evidenced towards the tested reactive oxygen species. Conclusions: No reactivity via H-atom transfer was evidenced for all studied compounds, suggesting that an antiradical activity should be excluded. Some reactivity only with strong oxidants could be predicted via electron- transfer. The acclaimed HO% scavenging activity should be interpreted in these terms. The study suggested that CAF might be hardly considered an antioxidant. General significance: Beyond the experimental methods used, the discussion of the present results might provide food for thought to the wide audience working on antioxidants.