Rottlerin: Structure Modifications and KCNQ1/KCNE1 Ion Channel Activity

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.

Molecular simulations reveal a mechanism for enhanced allosteric coupling between voltage-sensor and pore domains in KCNQ1 explaining its activation by ML277

“…In addition to auxiliary proteins and lipid cofactors, different small-molecule modulators of KCNQ1 have been reported in the literature. Zinc pyrithione (19) and L-364,373 (R-L3) (20) activate homomeric KCNQ1 channels, mefenamic acid (21), 4,4’-diisothiocyano-2,2’-stilbenedisulfonic acid (22), and rottlerin (23) activate the KCNQ1-KCNE1 complex, and phenylboronic acid (24), hexachlorophene (25), and 3-ethyl-2-hydroxy-2-cyclopenten-1-one (26) potentiate both KCNQ1 and KCNQ1-KCNE1. While some of these activators are able to shorten the action potential duration in isolated cardiac myocytes (20, 25), they have low potency and are not selective against other members of the KCNQ family or the hERG potassium channel.…”

Development of dye‐sensitized solar cell using M. philippensis (kamala tree) fruit extract: A combined experimental and theoretical study

“…The plant is commonly known as Kamala, red Kamala, or Kumkum tree, which contains rottlerin as its main constituent along with red compound as photoresponsive materials with other minor non-photoresponsive compounds in pericarp of its seeds. [20][21][22][23][24] Sharma et al studied kamala and reported rottlerin as its main compound (47.8%), the red and yellow compound observed in kamala extract were identified as 3-hydroxyrottlerin and 3,4-hydroxy rottlerin. 20 The plant has been established in many pharmaceutical use such as cancer, anti-microfilaria, and dermatology.…”

“…Mallotus phillipensis is a plant from the Euphorbiaceae family, which is commonly found in East Asia. The plant is commonly known as Kamala, red Kamala, or Kumkum tree, which contains rottlerin as its main constituent along with red compound as photoresponsive materials with other minor non‐photoresponsive compounds in pericarp of its seeds 20‐24 . Sharma et al studied kamala and reported rottlerin as its main compound (47.8%), the red and yellow compound observed in kamala extract were identified as 3‐hydroxyrottlerin and 3,4‐hydroxy rottlerin 20 .…”