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

ChemMedChem 2020 Jun 17

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The slow delayed rectifier potassium current (IKs ) is formed by the KCNQ1 (Kv 7.1) channel, an ion channel of four α-subunits that modulates KCNE1 β-subunits. IKs is central to the repolarization of the cardiac action potential. Loss of function mutation reducing ventricular cardiac IKs 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 IKs 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 IKs activators as novel therapeutics for the treatment of LQTS. © 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

Citation

Marco Lübke, Julian A Schreiber, Thang Le Quoc, Florian Körber, Jasmin Müller, Sivatharushan Sivanathan, Veronika Matschke, Janina Schubert, Nathalie Strutz-Seebohm, Guiscard Seebohm, Jürgen Scherkenbeck. Rottlerin: Structure Modifications and KCNQ1/KCNE1 Ion Channel Activity. ChemMedChem. 2020 Jun 17;15(12):1078-1088