Vasorelaxant and antioxidant activity of flavonols and flavones: structure-activity relationships

We investigated the structure-activity relationships regarding vascular and antioxidant activity of a range of synthetic flavonols and flavones with 3 or fewer hydroxyl (OH) or methoxyl substitutions. The relaxant responses and ability of the flavones/flavonols to inhibit phenylephrine (PE)- and Ca-induced contraction was determined in rat isolated thoracic aorta. The ability of these compounds to reduce the level of superoxide and preserve endothelium-dependent relaxation in the presence of oxidative stress was also examined. Four compounds impaired contraction to PE or Ca, in the potency order 3'-hydroxyflavonol>3',4'-dihydroxyflavonol>7,4'-dihydroxyflavonol>3',4'-dihydroxyflavone. Flavonol, 3',4'-dimethoxyflavonol, and flavone were significantly less active. The flavonoids caused concentration-dependent reductions in superoxide produced by rat aorta in the presence of NADPH. The most active compounds, 3',4'-dihydroxyflavonol and 7,4'-dihydroxyflavonol, preserved endothelium-dependent relaxation in the presence of oxidative stress caused by pyrogallol or xanthine/xanthine oxidase. The results indicate that the catechol group is not critical for vascular relaxant or antioxidant activity, but rather, the important determinants for higher vascular and antioxidant activity of these compounds are the presence of a C3 OH group and the total number of OH substituents, respectively. These results have allowed the identification of the structural characteristics that promote vascular and antioxidant activity of flavonols, which may lead to the development of agents useful in treatment of cardiovascular disease.