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.
The term ‘scavengome’ refers to the chemical space of all the metabolites that may be formed from an antioxidant upon scavenging reactive oxygen or nitrogen species (ROS/RNS). This chemical space is very rich in structures representing an increased chemical complexity as compared to the parent antioxidant: a wide range of unusual heterocyclic structures, new C-C bonds, etc. may be formed. Further, in a biological environment, this increased chemical complexity is directly translated from the localized conditions of oxidative stress that determines the amounts and types of ROS/RNS present. Biomimetic oxidative chemistry provides an excellent tool to model chemical reactions between antioxidants and ROS/RNS. In this chapter, we provide an overview on the known metabolites obtained by biomimetic oxidation of a few selected natural antioxidants, i.e., a stilbene (resveratrol), a pair of hydroxycinnamates (caffeic acid and methyl caffeate), and a flavonol (quercetin), and discuss the drug discovery perspectives of the related chemical space.
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