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.