Oxidized Resveratrol Metabolites as Potent Antioxidants and Xanthine Oxidase Inhibitors

Abstract

Resveratrol is a well-known natural polyphenol with a plethora of pharmacological activities. As a potent antioxidant, resveratrol is highly oxidizable and readily reacts with reactive oxygen species (ROS). Such a reaction not only leads to a decrease in ROS levels in a biological environment but may also generate a wide range of metabolites with altered bioactivities. Inspired by this notion, in the current study, our aim was to take a diversity-oriented chemical approach to study the chemical space of oxidized resveratrol metabolites. Chemical oxidation of resveratrol and a bioactivity-guided isolation strategy using xanthine oxidase (XO) and radical scavenging activities led to the isolation of a diverse group of compounds, including a chlorine-substituted compound (2), two iodine-substituted compounds (3 and 4), two viniferins (5 and 6), an ethoxy-substituted compound (7), and two ethoxy-substitute,0d dimers (8 and 9). Compounds 4, 7, 8, and 9 are reported here for the first time. All compounds without ethoxy substitution exerted stronger XO inhibition than their parent compound, resveratrol. By enzyme kinetic and in silico docking studies, compounds 2 and 4 were identified as potent competitive inhibitors of the enzyme, while compound 2 and the viniferins acted as mixed-type inhibitors. Further, compounds 2 and 9 had better DPPH scavenging activity and oxygen radical absorbing capacity than resveratrol. Our results suggest that the antioxidant activity of resveratrol is modulated by the effect of a cascade of chemically stable oxidized metabolites, several of which have significantly altered target specificity as compared to their parent compound.

Resveratrol Supplements Reduce the Risk of Aging-Related Cardiac Disease after Cardiorespiratory Fitness

“…Cardiorespiratory fitness training improves the vasodilatory properties of the vasculature thereby optimizing O 2 transport throughout the body [18]. Regular Cardiorespiratory fitness also improves vascular function in association with the reduction of reactive oxygen species.…”

Therapeutic voyage of synthetic and natural xanthine oxidase inhibitors

“…Finally, molecular simulations uncovered the interaction of hesperidin derivatives with the amino acid residues Phe798, Gln1194, Arg912, Thr585, Ser1080, and Met1038 present in the binding site of XO (Malik et al, 2019). Agbadua et al (2022) prepared metabolites from the oxidation of resveratrol to evaluate XO inhibition. Among the isolated substances, 2 and 4 inhibited XO with higher potency with an IC 50 value of 4.8 ± 0.8 μM and 6.4 ± 0.5 μM, respectively, and displayed efficacy analog to that of positive control allopurinol (IC 50 = 5.9 ± 0.9 μM).…”

“…as XO inhibitors (Agbadua et al, 2022). The structures of semisynthetic derivatives displaying XO inhibitory activity are shown in Figure 6.…”

“…Agbadua et al (2022) prepared metabolites from the oxidation of resveratrol to evaluate XO inhibition. Among the isolated substances, 2 and 4 inhibited XO with higher potency with an IC 50 value of 4.8 ± 0.8 μM and 6.4 ± 0.5 μM, respectively, and displayed efficacy analog to that of positive control allopurinol (IC 50 = 5.9 ± 0.9 μM).…”

Molecular docking and experimental validation of the effect of ergothioneine on heat shock protein-70 following endurance exercise by Arabian stallions

“…They do this in four ways: 1) by neutralizing free radicals, 2) by repairing oxidized membranes, 3) by reducing the production of reactive oxygen species, and 4) by neutralizing reactive oxygen species through lipid metabolism [7]. Exogenous antioxidants have received signi cant attention for their potential to prevent or reduce oxidative stress, minimize physical stress and muscle pain, and improve athletic performance [8,9].…”