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. 2020 Jun 17;15(12):1078-1088.
doi: 10.1002/cmdc.202000083. Epub 2020 May 5.

Rottlerin: Structure Modifications and KCNQ1/KCNE1 Ion Channel Activity

Marco Lübke  1 , Julian A Schreiber  2 , Thang Le Quoc  3 , Florian Körber  1 , Jasmin Müller  1 , Sivatharushan Sivanathan  1 , Veronika Matschke  4 , Janina Schubert  2 , Nathalie Strutz-Seebohm  2 , Guiscard Seebohm  2 , Jürgen Scherkenbeck  1
Affiliations

Rottlerin: Structure Modifications and KCNQ1/KCNE1 Ion Channel Activity

Marco Lübke et al. ChemMedChem. .

Abstract

The slow delayed rectifier potassium current (IKs ) is formed by the KCNQ1 (Kv 7.1) 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.

Keywords: mode of action; natural product rottlerin; potassium channel KCNQ1 activator; total synthesis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structures of rottlerin (1) and rottlerone (2).
Scheme 1
Scheme 1
Total synthesis of rottlerin (1) and derivatives 8 b–f.
Figure 2
Figure 2
Rottlerin derivatives by modification of the natural product.
Figure 3
Figure 3
A)–D) Voltage dependent activation of KCNQ1/KCNE1 channels in absence (control, ctr) and presence of rottlerin (1) and analogs 8 b–d. Compounds were applied at 10 and 30 μM, and the effect on steady‐state activated current amplitude was assessed at different voltages. Current amplitudes were normalized to the mean of amplitudes at +40 mV in absence of test compounds (control) E)‐I) Mean of normalized current amplitudes±SEM of different voltage steps in absence (ctr) and presence of rottlerin (1) and 8 b–d. The number of independent experimental data points are given in Table 2. Significance of mean differences was determined by one‐way ANOVA and post‐hoc mean comparison Tukey test (ns: p>0.05, *p<0.05, **p<0.01, ***p<0.001).
Figure 4
Figure 4
Relation of KCNQ1/KCNE1 deactivation time constants in the presence of rottlerin (1) and compounds 8 b–8 d (τ compound) compared to absence of compounds (τ control). Time constants of deactivation were determined as described in the Experimental Section. Values are given as mean ±SEM. The significance of mean differences was determined by one‐way ANOVA and post‐hoc mean comparison Tukey test (ns: p>0.05, *p<0.05, **p<0.01, ***p<0.001).
Figure 5
Figure 5
Normalized current amplitudes of KCNQ1/KCNE1‐expressing oocytes in the presence of 30 μM of compounds 9 and 10. The effect of derivatives on KCNQ1/KCNE1 currents was determined as described above and are shown as mean±SEM (n=9–12, unpaired t‐test **p<0.01, ***p<0.001).
Figure 6
Figure 6
a) Structure of a KCNQ1 subunit and potential binding sites for small molecules. b) open KCNQ1 channel (6V01, PIP2 bound, human), c) closed KCNQ1 channel (6UZZ, human).
Figure 7
Figure 7
Structures of published KCNQ1 ligands.
Figure 8
Figure 8
a) Superposition of thiophene rottlerin 8 d and PIP2. b) Superposition of rottlerin and PIP2. c) Orientation of rottlerin (orange) and PIP2 (green) in the Arg243 site. According to the cryo‐EM structure 6V01, PIP2 contains heptanoic acid in sn1 position and (5E,8E,11E,14Z)‐hexadecatetraenoic acid in position sn2.
Figure 9
Figure 9
a) Open‐channel binding‐pocket around Ile337 (PDB ID: 6V01) with bound trifluoromethoxyphenyl rottlerin 8 b. Colors code protein chains. b) Closed‐channel Ile337 binding pocket (PDB ID: 6UZZ) with bound benzodiazepinone 14. Colors code protein chains. c) Open‐channel structure with residues found important for rottlerin and benzodiazepinone 14 binding (PDB ID: 6V01). d) Closed‐channel structure with residues found essential for rottlerin and benzodiazepinone 14 binding (PDB ID: 6UZZ).
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