Discovery of relaxant flavonols without antioxidant activity

Abstract

3′,4′‐dihydroxyflavonol (DiOHF) is an antioxidant and vasorelaxant that reduces injury after ischaemia and reperfusion. We synthesized a series of compounds based on DiOHF with pharmacophore modifications at the 3′ and 4′ positions on the B ring and examined the biological activity for the 18 novel flavonols [4′‐substituted flavonols (H; OH; OMe; Me; Cl; CF3; C(CH3) 3); 3′‐substituted flavonols (H; OH; OMe; Me; Cl; CF3) and 4′‐hydroxy‐3′‐substituted flavonols (H; OH; OMe; Me; Br; CF3; C(CH3) 3)]. Each flavonol was examined for its ability to relax rat isolated aortic rings precontracted with KCl (30 mM). The most active flavonols (Rmax>80%) were those with a hydroxy group at the 4′ position (eg, DiOHF, pEC50=5.30±0.07, Rmax=102±1%; 4′‐OH‐3′‐OCH3 flavonol, 5.35±0.03, 98±2%; 4′‐OCH3 flavonol, Rmax=37±4%). The antioxidant activity of each flavonol was then assessed by lucigenin‐enhanced chemiluminescence and assays to assess endothelial dysfunction due to oxidant stress. With the exception of DiOHF, none of these flavonols (at 10‐5 M) were able to significantly scavenge superoxide radical or prevent pyrogallol or xanthine/xanthine oxidase‐induced endothelial dysfunction. The discovery of vasorelaxant flavonols without antioxidant activity, such as 4′‐OH‐3′‐OCH3 flavonol, will assist in investigating the mechanism of flavonol‐induced cardioprotection.