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

- Flavonoid derivatives quercetin, fisetin, and luteolin are potent hERG K+ channel inhibitors.
- The present work reveal the structure-activity relationship of natural flavonoids.
- The results also provide new mechanistic evidence for understanding the effects of these natural products.

ObjectivesFlavonoids 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-à-go-go-related gene (hERG) K+ channels.Key findingsIn 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 (IC50) and maximum efficacy (Emax) 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.ConclusionThese results suggest that quercetin, fisetin, and luteolin are potent hERG K+ channel inhibitors and reveal the structure-activity relationship of natural flavonoids.