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.
