Modeling the antioxidant behavior of F420 coenzyme: a computational study

Abstract

8-Hydroxy-10-methylpyrimido[4,5-b]quinoline-2,4(3H,10H)-dione (F0) and the structurally very similar reductive F0 coenzyme (F0H2), the molecule equivalent of the active center of the F₄₂₀ coenzyme, are known to be potent radical scavengers. F0 and F0H2 are also valuable models of F₄₂₀ activity. In spite of that F0/F0H2 received little attention thus far. Despite the initial reports of their substantial antioxidant activity, the mechanism and kinetics of their radical scavenging activity have not been examined. In this study, the HO˙ and HOO˙ scavenging properties of F0/F0H2 were evaluated in physiological environments using quantum chemical calculations. It was found that both compounds are effective HO˙ scavengers in lipid as well as polar media (k = 1.60 × 10⁹, 7.46 × 10⁹ and 1.88 × 10¹⁰, 2.95 × 10¹⁰ M⁻¹ s⁻¹ for F0 and F0H2 in the lipid and polar media, respectively). In the lipid medium, the hydroxyl radical scavenging activity followed the formal hydrogen transfer mechanism at the O8–H/C5–H bonds, while in the polar medium, the activity was characterized by the sequential electron transfer proton transfer and radical adduct formation reactions of the anion state. In terms of the HOO˙ antiradical activity, F0 was found to be a weak antioxidant, whereas F0H2 presented excellent HOO˙ scavenging activity, particularly in the aqueous media. It was found that the radical products may react with the O₂˙⁻ radical with rate constants of 2.04 × 10⁷ and 5.98 × 10⁹ M⁻¹ s⁻¹, respectively for F0 and F0H2; this secondary reaction likely underpins the protective effect of F0/F0H2 against oxidative stress.