Oxidized Resveratrol Metabolites as Potent Antioxidants and Xanthine Oxidase Inhibitors.

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 (), two iodine-substituted compounds ( and ), two viniferins ( and ), an ethoxy-substituted compound (), and two ethoxy-substitute,0d dimers ( and ). Compounds , , , and 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 and were identified as potent competitive inhibitors of the enzyme, while compound and the viniferins acted as mixed-type inhibitors. Further, compounds and 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.