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

Abstract

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'-NO(2)-4-HS), and 4-hydroxy-4'-trifluoromethyl-trans-stilbene (4'-CF(3)-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 degrees 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.

Details of the antioxidant mechanism of hydroxycinnamic acids

“…This modification can be explained based on the fact that a proton is first lost by an acid-base equilibrium to give the phenoxide anion followed by a very fast electron transfer from these species to radical (SPLET). According to their approach, we also confirm by studying the effect of added acetic acid on the measured rate constant that the radical-scavenging reaction of resveratrol analogues in ethanol primarily involved the SPLET mechanism (Shang et al 2009). Hydroxycinnamic acid derivatives, which are relatively strong acids, are in equilibrium with the carboxylic anion and H + in methanol that supports ionisation.…”

“…Sensors l scavenging activity and antioxidant mechanism of chalcones and resveratrol analogues by studying the influences of solvents, radicals, and substitutions on the antioxidant activity (Shang et al 2009;Qian et al 2011). Hydroxycinnamic acids are organic acids, with pK a values ranging from 4 to 5 (Beltrán et al 2003).…”

Hybrid‐Increased Radical‐Scavenging Activity of Resveratrol Derivatives by Incorporating a Chroman Moiety of Vitamin E

“…[4a, 6] Recently, we found that introduction of electron-donating substituents in the ortho-or para-position of the 4'-OH could significantly enhance its antioxidant activity, [7] prooxidant activity on DNA damage in the presence of Cu II ions, [8] and cytotoxicity on human promeolocytic leukemia cells. [9] The hybrid approach has recently attracted much attention in medicinal chemistry and design of hybrid molecules encompassing two pharmacophores in one molecular scaffold is a niche area in a large field of drug discovery.…”

The Protective Role Of Resveratrol On Serum Total Sialic Acid And Lipid-Bound Sialic Acid In Female Rats With Chronic Fluorosis

“…Resveratrol is believed to have the various biological abilities such as antioxidant and anti-inflammatory effects (4). Previous experiments have shown that resveratrol is able to scavenge free radicals directly by hydrogen atom transfer and sequential proton loss electron transfer (5,6). Resveratrol has the anti-tumor effect against various cancer types due to inhibition of cell proliferation, induce apoptosis and suppress metastasis and invasion in a number of cell lines.…”