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

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

  • Bioorg Chem. 2020 Dec;105:104404. doi: 10.1016/j.bioorg.2020.104404.
Gabriele Carullo 1,  Amer Ahmed 2,  Alfonso Trezza 3,  Ottavia Spiga 3,  Antonella Brizzi 3,  Simona Saponara 4,  Fabio Fusi 5,  Francesca Aiello 6
Affiliations

Affiliations

  • 1 Department of Pharmacy, Health and Nutritional Sciences, DoE 2018-2022, University of Calabria, Edificio Polifunzionale, 87036 Rende (CS), Italy; Department of Biotechnology, Chemistry and Pharmacy, DoE 2018-2022, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
  • 2 Department of Life Sciences, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
  • 3 Department of Biotechnology, Chemistry and Pharmacy, DoE 2018-2022, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
  • 4 Department of Life Sciences, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy. Electronic address: simona.saponara@unisi.it.
  • 5 Department of Biotechnology, Chemistry and Pharmacy, DoE 2018-2022, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy. Electronic address: fabio.fusi@unisi.it.
  • 6 Department of Pharmacy, Health and Nutritional Sciences, DoE 2018-2022, University of Calabria, Edificio Polifunzionale, 87036 Rende (CS), Italy.
PMID: 33142229 DOI: 10.1016/j.bioorg.2020.104404
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.

Keywords

Ca(V)1.2 channel; Ester-based derivatives; Hypertension; K(Ca)1.1 channel; Lipoic acid; Molecular docking; Quercetin; Vasoactivity.

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