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 3 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.

Keywords: NMR spectroscopy; antioxidant metabolism; bioactivity-guided isolation; biomimetic oxidation; resveratrol; scavengome; xanthine oxidase.

Figure 1

Structures of resveratrol (1) and its metabolites obtained by chemical oxidation (2–9). Each optically active compound (5, 6, 8, 9) is racemate; for simplicity, only one enantiomer is presented. For compounds 7 and 9, the relative configuration could not be determined.

Figure 2

Best-docked poses of compounds 2 (A) and 4 (B). Three-dimensional orientation and aromatic edge/face receptor surface is shown for both compounds at identical viewing angle and zoom (left), along with the 2D interpretation of the ligand–residue interactions with the 3NVY protein (right).