Agbadua Orinamhe G, Kúsz Norbert, Berkecz Róbert, Gáti Tamás, Tóth Gábor, Hunyadi Attila
Institute of Pharmacognosy, University of Szeged, H-6720 Szeged, Hungary.
Institute of Pharmaceutical Analysis, University of Szeged, H-6720 Szeged, Hungary.
Antioxidants (Basel). 2022 Sep 17;11(9):1832. doi: 10.3390/antiox11091832.
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.
白藜芦醇是一种广为人知的天然多酚，具有多种药理活性。作为一种强效抗氧化剂，白藜芦醇具有高度可氧化性，能与活性氧（ROS）迅速反应。这种反应不仅会导致生物环境中ROS水平降低，还可能产生一系列生物活性改变的代谢产物。受此启发，在本研究中，我们旨在采用一种以多样性为导向的化学方法来研究氧化白藜芦醇代谢产物的化学空间。通过白藜芦醇的化学氧化以及使用黄嘌呤氧化酶（XO）和自由基清除活性的生物活性导向分离策略，分离出了一组多样的化合物，包括一种氯取代化合物（）、两种碘取代化合物（和）、两种葡萄素（和）、一种乙氧基取代化合物（）以及两种乙氧基取代的二聚体（和）。化合物、、、和在此首次报道。所有无乙氧基取代的化合物对白藜芦醇氧化酶的抑制作用均强于其母体化合物白藜芦醇。通过酶动力学和计算机模拟对接研究，化合物和被鉴定为该酶的强效竞争性抑制剂，而化合物和葡萄素则作为混合型抑制剂。此外，化合物和的二苯基苦味酰基自由基（DPPH）清除活性和氧自由基吸收能力均优于白藜芦醇。我们的结果表明，白藜芦醇的抗氧化活性受到一系列化学稳定的氧化代谢产物的影响，其中一些代谢产物与其母体化合物相比具有显著改变的靶标特异性。
