Discovery of water-soluble antioxidant flavonols without vasorelaxant activity

Abstract

3',4'-Dihydroxyflavonol (DiOHF) is a cardioprotective flavonol that can decrease ischaemia/reperfusion injury in the heart. DiOHF exhibits antioxidant and vasorelaxant properties that are thought to underlie its cardioprotective activity. A major limitation to its use for the treatment or prevention of cardiovascular disease is its poor water solubility, preventing intravenous administration at the required dosage. In this study, three novel flavonols were synthesised that bear an ionisable succinamic acid substituent at the 6-position of the A ring with zero, one, or two hydroxy groups on the B ring. The ionised compounds possess improved aqueous solubility, dissolving at concentrations up to 10(-1) m, whereas DiOHF is insoluble in water (<10(-7) m). Pharmacological analysis revealed that the DiOHF-6-succinamic acid derivative was the best antioxidant, possessing activity similar to DiOHF, whereas vasorelaxant activity was attenuated. This compound was able to effectively scavenge superoxide from the autoxidation of pyrogallol, preventing oxidant-induced endothelial dysfunction. DiOHF-6-succinamic acid represents the first antioxidant flavonol that lacks vasorelaxant activity and in the future will enable studies to cast light on the specific biological activity required for cardioprotection.