Quercetin represents one of the most studied dietary flavonoids; it exerts a panel of pharmacological activities particularly on the cardiovascular system. Stimulation of vascular KCa1.1 channels contributes to its vasorelaxant activity, which is, however, counteracted in part by its concomitant stimulation of CaV1.2 channels. Therefore, several quercetin hybrid derivatives were designed and synthesized to produce a more selective KCa1.1 channel stimulator, then assessed both in silico and in vitro. All the derivatives interacted with the KCa1.1 channel with similar binding energy values. Among the selected derivatives, 1E was a weak vasodilator, though displaying an interesting CaV1.2 channel blocking activity. The lipoyl derivatives 1F and 3F, though showing pharmacological and electrophysiological features similar to those of quercetin, seemed to be more effective as KCa1.1 channel stimulators as compared to the parent compound. The strategy pursued demonstrated how different chemical substituents on the quercetin core can change/invert its effect on CaV1.2 channels or enhance its KCa1.1 channel stimulatory activity, thus opening new avenues for the synthesis of efficacious vasorelaxant quercetin hybrids.

Design, synthesis and pharmacological evaluation of ester-based quercetin derivatives as selective vascular KCa1.1 channel stimulators

Carullo G.;Aiello F.
2020

Abstract

Quercetin represents one of the most studied dietary flavonoids; it exerts a panel of pharmacological activities particularly on the cardiovascular system. Stimulation of vascular KCa1.1 channels contributes to its vasorelaxant activity, which is, however, counteracted in part by its concomitant stimulation of CaV1.2 channels. Therefore, several quercetin hybrid derivatives were designed and synthesized to produce a more selective KCa1.1 channel stimulator, then assessed both in silico and in vitro. All the derivatives interacted with the KCa1.1 channel with similar binding energy values. Among the selected derivatives, 1E was a weak vasodilator, though displaying an interesting CaV1.2 channel blocking activity. The lipoyl derivatives 1F and 3F, though showing pharmacological and electrophysiological features similar to those of quercetin, seemed to be more effective as KCa1.1 channel stimulators as compared to the parent compound. The strategy pursued demonstrated how different chemical substituents on the quercetin core can change/invert its effect on CaV1.2 channels or enhance its KCa1.1 channel stimulatory activity, thus opening new avenues for the synthesis of efficacious vasorelaxant quercetin hybrids.
Ca
V
1.2 channel
Ester-based derivatives
Hypertension
K
Ca
1.1 channel
Lipoic acid
Molecular docking
Quercetin
Vasoactivity
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11770/310553
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