Structure–activity relationship studies of resveratrol and its analogues by the reaction kinetics of low density lipoprotein peroxidation

Resveratrol (3,5,4′-trans-trihydroxystibene) is a natural phytoalexin present in grapes and red wine, which possesses a variety of biological activities including antioxidative activity. To find more active antioxidants, with resveratrol as the lead compound, we synthesized resveratrol analogues, i.e., 3,4,3′,4′-tetrahydroxy-trans-stilbene (3,4,3′,4′-THS), 3,4,4′-trihydroxy-trans-stilbene (3,4,4′-THS), 2,4,4′-trihydroxy-trans-stilbene (2,4,4′-THS), 3,3′-dimethoxy-4,4′-dihydroxy-trans-stilbene (3,3′-DM-4,4′-DHS), 3,4-dihydroxy-trans-stilbene (3,4-DHS), 4,4′-dihydroxy-trans-stilbene (4,4′-DHS), 3,5-dihydroxy-trans-stilbene (3,5-DHS) and 2,4-dihydroxy-trans-stilbene (2,4-DHS). Antioxidative effects of resveratrol and its analogues against free-radical-induced peroxidation of human low density lipoprotein (LDL) were studied. The peroxidation was initiated either by a water-soluble initiator 2,2′-azobis(2-amidinopropane hydrochloride) (AAPH), or by cupric ion (Cu2+). The reaction kinetics were monitored either by the uptake of oxygen and the depletion of α-tocopherol (TOH) presented in the native LDL, or by the formation of thiobarbituric acid reactive substances (TBARS). Kinetic analysis of the antioxidation process demonstrates that these trans-stilbene derivatives are effective antioxidants against both AAPH- and Cu2+-induced LDL peroxidation with the activity sequence of 3,4,3′,4′-THS ∼ 3,3′-DM-4,4′-DHS > 3,4-DHS ∼ 3,4,4′-THS > 2,4,4′-THS > resveratrol ∼ 3,5-DHS > 4,4′-DHS ∼ 2,4-HS, and 3,4,3′,4′-THS ∼ 3,4-DHS ∼ 3,4,4′-THS > 3,3′-DM-4,4′-DHS > 4,4′-DHS > resveratrol ∼ 2,4-HS > 2,4,4′-THS ∼ 3,5-DHS, respectively. Molecules bearing ortho-dihydroxyl or 4-hydroxy-3-methoxyl groups possess significantly higher antioxidant activity than those bearing no such functionalities.

The “French paradox,” a low incidence of cardiovascular disease despite a high fat intake, is believed to be associated with the high content of resveratrol, the antioxidative components in red wine. To find more active antioxidants with resveratrol as the lead compound we synthesized resveratrol analogues. Antioxidative effects of resveratrol and its analogues against free-radical-induced peroxidation of human low density lipoprotein (LDL) were studied. The compounds bearing ortho-dihydroxyl or 4-hydroxy-3-methoxyl functionality exhibit remarkably higher antioxidative activity than the ones bearing no such functionalities.Figure optionsDownload as PowerPoint slide