Abstract
The slow delayed rectifier potassium current (IKs) is formed by the KCNQ1 (Kv7.1) channel, an ion channel of four α‐subunits that modulates KCNE1 β‐subunits. IKs is central to the repolarization of the cardiac action potential. Loss of function mutation reducing ventricular cardiac IKs 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 IKs 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 IKs activators as novel therapeutics for the treatment of LQTS.
Highlights
We identified rottlerin as a potent KCNQ1 and KCNQ4 activator.[11]
We describe the first rottlerin derivatives, obtained by derivatization of the natural product and total synthesis
The structure of rottlerin is known for decades, the first two total syntheses were published only recently
Summary
The structure of rottlerin is known for decades, the first two total syntheses were published only recently. Since the styrene pocket is too small to accommodate a substituted benzene ring, the preferred orientation of both compounds is an optimal match of the more lipophilic arene side chains with the unsaturated side chain of PIP2 In this arrangement, the chromene unit serves as a mimic for the inositol-ring with the pyrane oxygen situated close to or in the pocket of the inositol-4-phosphate group, while the partially negatively charged trihydroxyphenyl ring imitates the 5phosphate residue. The pocket in the open state (PDB ID: 6V01) overlaps with the binding site of the PIP2 unsaturated chain and has a high affinity for rottlerin and derivatives 8 b–d. It consists of two interconnected crevices, which accommodate the two aromatic side chains of rottlerin (Figure 9). Larger phenyl substituents cause a reorientation of the rottlerin derivative in the Arg243 binding site, mimicking the unsaturated PIP2 side chain, which contributes only via weak lipophilic interactions to the overall binding energy
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