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

Authors :
Lübke M
Schreiber JA
Le Quoc T
Körber F
Müller J
Sivanathan S
Matschke V
Schubert J
Strutz-Seebohm N
Seebohm G
Scherkenbeck J
Source :
ChemMedChem [ChemMedChem] 2020 Jun 17; Vol. 15 (12), pp. 1078-1088. Date of Electronic Publication: 2020 May 05.
Publication Year :
2020

Abstract

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

Details

Language :
English
ISSN :
1860-7187
Volume :
15
Issue :
12
Database :
MEDLINE
Journal :
ChemMedChem
Publication Type :
Academic Journal
Accession number :
32338831
Full Text :
https://doi.org/10.1002/cmdc.202000083