Radical-Scavenging Activity and Mechanism of Resveratrol-Oriented Analogues: Influence of the Solvent, Radical, and Substitution

• Published in: Journal of organic chemistry Vol. 74; no. 14; pp. 5025 - 5031
• Main Authors: Shang, Ya-Jing, Qian, Yi-Ping, Liu, Xiao-Da, Dai, Fang, Shang, Xian-Ling, Jia, Wen-Qiang, Liu, Qiang, Fang, Jian-Guo, Zhou, Bo
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 17.07.2009
• Subjects: Acetates - chemistry; Antioxidants - chemistry; Antioxidants - pharmacology; Chemistry; Ethanol - chemistry; Exact sciences and technology; Free Radicals - chemistry; Heterocyclic compounds; Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives; Kinetics; Kinetics and mechanisms; Molecular Structure; Noncondensed benzenic compounds; Organic chemistry; Preparations and properties; Reactivity and mechanisms; Solvents - chemistry; Stilbenes - chemistry; Stilbenes - pharmacology; Structure-Activity Relationship; Nitro compound; Furan derivatives; Electron transfer; Oxygen heterocycle; Phenoxy radical; Radical trapping; Resveratrol; Hydroxyl group; Reaction mechanism; Oxidation; Rate constant; Chemical synthesis; Solvent; Hydrogen transfer; Dioxane derivatives; Ethanol; DPPH; Quinone; Reduction potential; Malignant tumor; Antioxidant; Acetic acid derivative; Reaction rate; Chemical reaction kinetics; Stilbene derivatives; Ionization; Phytoalexin; Organic free radical; Analog; Phenols; Benzenic compound; Dimer; Fluorine Organic compounds; Acetic acid; Cancer; Ultraviolet visible spectrometry
• DOI: 10.1021/jo9007095
• ISSN: 0022-3263; 1520-6904

Resveratrol (3,5,4′-trihydroxy-trans-stilbene, 3,5,4′-THS) is a well-known natural antioxidant and cancer chemopreventive agent that has attracted much interest in the past decade. To find a more active antioxidant and investigate the antioxidative mechanism with resveratrol as the lead compound, we synthesized 3,5-dihydroxy-trans-stilbene (3,5-DHS), 4-hydroxy-trans-stilbene (4-HS) 3,4-dihydroxy-trans-stilbene (3,4-DHS), 4,4′-dihydroxy-trans-stilbene (4,4′-DHS), 4-hydroxy-3-methoxy-trans-stilbene (3-MeO-4-HS), 4-hydroxy-4′-methoxy-trans-stilbene (4′-MeO-4-HS), 4-hydroxy-4′-methyl-trans-stilbene (4′-Me-4-HS), 4-hydroxy-4′-nitro-trans-stilbene (4′-NO2-4-HS), and 4-hydroxy-4′-trifluoromethyl-trans-stilbene (4′-CF3-4-HS). The radical-scavenging activity and detailed mechanism of resveratrol and its analogues (ArOHs) were investigated by the reaction kinetics with galvinoxyl (GO•) and 2,2-diphenyl-1-picrylhydrazyl (DPPH•) radicals in ethanol and ethyl acetate at 25 °C, using UV−vis spectroscopy. It was found that the reaction rates increase with increasing the electron-rich environment in the molecules, and the compound bearing o-dihydroxyl groups (3,4-DHS) is the most reactive one among the examined resveratrol analogues. The effect of added acetic acid on the measured rate constant for GO• -scavenging reaction reveals that in ethanol that supports ionization solvent besides hydrogen atom transfer (HAT), the kinetics of the process is partially governed by sequential proton loss electron transfer (SPLET). In contrast to GO•, DPPH• has a relatively high reduction potential and therefore enhances the proportion of SPLET in ethanol. The relatively low rate constants for the reactions of ArOHs with GO• or DPPH• in ethyl acetate compared with the rate constants in ethanol prove that in ethyl acetate these reactions occur primarily by the HAT mechanism. The contribution of SPLET and HAT mechanism depends on the ability of the solvent to ionize ArOH and the reduction potential of the free radical involved. Furthermore, the fate of the ArOH-derived radicals, i.e., the phenoxyl radicals, was investigated by the oxidative product analysis of ArOHs and GO• in ethanol. The major products were dihydrofuran dimers in the case of resveratrol, 4,4′-DHS, and 4-HS and a dioxane-like dimer in the case of 3,4-DHS. It is suggested from the oxidative products of these ArOHs that the hydroxyl group at the 4-position is much easier to subject to oxidation than other hydroxyl groups, and the dioxane-like dimer is formed via an o-quinone intermediate.