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 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.