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.