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Rottlerin: Structure Modifications and KCNQ1/KCNE1 Ion Channel Activity.
- 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.)
- Subjects :
- Acetophenones chemical synthesis
Acetophenones metabolism
Animals
Benzopyrans chemical synthesis
Benzopyrans metabolism
Binding Sites
Humans
KCNQ1 Potassium Channel metabolism
Molecular Docking Simulation
Oocytes drug effects
Protein Binding
Xenopus laevis
Acetophenones pharmacology
Benzopyrans pharmacology
KCNQ1 Potassium Channel agonists
Potassium Channels, Voltage-Gated agonists
Xenopus Proteins agonists
Subjects
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