Specific structural determinants are responsible for the antioxidant activity and the cell cycle effects of resveratrol

Resveratrol (3,4',5-trihydroxy-trans-stilbene) is a natural phytoalexin fou nd in grapes and wine, which shows antioxidant and antiproliferative activi ties. In this study we have investigated whether these properties are depen dent on similar or different structural determinants of the molecule. To th is purpose, resveratrol derivatives, in which all or each single hydroxylic function were selectively substituted with methyl groups, were synthesized . Analogues with the stilbenic double bond reduced or with the stereoisomer y modified were also investigated. The antioxidant activity of these compou nds was evaluated by measuring the inhibition of citronellal thermo-oxidati on, or the reduction of 2,2 diphenyl-1-picrylhydrazyl radical. In addition, the protection against lipid peroxidation was determined in rat liver micr osomes, and in human primary cell cultures. The antiproliferative activity was evaluated by a clonogenic assay, and by analysis of cell cycle progress ion and DNA synthesis. The results showed that the hydroxyl group in 4' pos ition is not the sole determinant for antioxidant activity. In contrast, th e presence of 4'-OH together with stereoisomery in the trans conformation ( 4'-hydroxystyryl moiety) was absolutely required for inhibition of cell pro liferation. Enzymatic assays in vitro demonstrated that inhibition of DNA s ynthesis was induced by a direct interaction of resveratrol with DNA polyme rases alpha and delta.