Rottlerin: Structure Modifications and KCNQ1/KCNE1 Ion Channel Activity.

Autor: Lübke M; Faculty of Mathematics and Natural Sciences, University Wuppertal, 42119, Wuppertal, Germany., Schreiber JA; Institut für Genetik von Herzerkrankungen, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany., Le Quoc T; Department of Chemistry, Hue University, 34 Le Loi St., Hue City, Vietnam., Körber F; Faculty of Mathematics and Natural Sciences, University Wuppertal, 42119, Wuppertal, Germany., Müller J; Faculty of Mathematics and Natural Sciences, University Wuppertal, 42119, Wuppertal, Germany., Sivanathan S; Faculty of Mathematics and Natural Sciences, University Wuppertal, 42119, Wuppertal, Germany., Matschke V; Medical Faculty, Institute of Anatomy Department of Cytology, Ruhr University Bochum, 44801, Bochum, Germany., Schubert J; Institut für Genetik von Herzerkrankungen, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany., Strutz-Seebohm N; Institut für Genetik von Herzerkrankungen, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany., Seebohm G; Institut für Genetik von Herzerkrankungen, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany., Scherkenbeck J; Faculty of Mathematics and Natural Sciences, University Wuppertal, 42119, Wuppertal, Germany.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2020 Jun 17; Vol. 15 (12), pp. 1078-1088. Date of Electronic Publication: 2020 May 05.
DOI: 10.1002/cmdc.202000083
Abstrakt: The slow delayed rectifier potassium current (I Ks ) is formed by the KCNQ1 (K v 7.1) channel, an ion channel of four α-subunits that modulates KCNE1 β-subunits. I Ks is central to the repolarization of the cardiac action potential. Loss of function mutation reducing ventricular cardiac I Ks cause the long-QT syndrome (LQTS), a disorder that predisposes patients to arrhythmia and sudden death. Current therapy for LQTS is inadequate. Rottlerin, a natural product of the kamala tree, activates I Ks and has the potential to provide a new strategy for rational drug therapy. In this study, we show that simple modifications such as penta-acetylation or penta-methylation of rottlerin blunts activation activity. Total synthesis was used to prepare side-chain-modified derivatives that slowed down KCNQ1/KCNE1 channel deactivation to different degrees. A binding hypothesis of rottlerin is provided that opens the way to improved I Ks activators as novel therapeutics for the treatment of LQTS.
(© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)
Databáze: MEDLINE
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