Characterization and structure-activity relationship of natural flavonoids as hERG K+ channel modulators

Abstract Objectives Flavonoids are present in varying concentrations in plant foods and have been reported to have numerous pharmacological activities, such as anti-cancer, antioxidant, anti-inflammatory, hepatoprotective, and vasodilator effects. We found that quercetin, fisetin, and some related flavonoid derivatives could inhibit human ether-a-go-go -related gene (hERG) K + channels. Key findings In this study, we tested the effects of a series of flavonoids on the hERG K + channel expressed in HEK293 cells. For the first time, we demonstrate that quercetin and fisetin (Fise) are potent hERG current blockers. The 50% inhibiting concentration (IC 50 ) and maximum efficacy (E max ) of quercetin were 11.8 ± 0.9 μM and 82 ± 2%, while those of fisetin were 38.4 ± 6 μM and 100 ± 6%, respectively. Luteolin (Lute) was a less potent inhibitor of hERG current (48 ± 1% at 100 μM). Galangin, kaempferol, and isorhamnetin (100 μM) showed weaker activity on the hERG currents. Conclusion These results suggest that quercetin, fisetin, and luteolin are potent hERG K + channel inhibitors and reveal the structure-activity relationship of natural flavonoids.