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

The slow delayed rectifier potassium current (I Ks ) is formed by the KCNQ1 (K v 7.1) channel, an ion channel bearing four α-subunits and modulating KCNE1 β-subunits. I Ks is central in 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. A total synthetic approach was used for the preparation of side chain modified derivatives, that slowed down KCNQ1/KCNE1 channel deactivation to different degrees. A binding hypothesis of rottlerin is provided, which opens the path for improved I Ks activators as novel therapeutics for the treatment of LQTS.