Rottlerin: Structure Modifications and KCNQ1/KCNE1 Ion Channel Activity.
Marco LübkeJulian A SchreiberThang Le QuocFlorian KörberJasmin MüllerSivatharushan SivanathanVeronika MatschkeJanina SchubertNathalie Strutz-SeebohmGuiscard SeebohmJürgen ScherkenbeckPublished in: ChemMedChem (2020)
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.
Keyphrases
- left ventricular
- end stage renal disease
- newly diagnosed
- heart failure
- chronic kidney disease
- ejection fraction
- prognostic factors
- dna methylation
- peritoneal dialysis
- small molecule
- magnetic resonance imaging
- emergency department
- binding protein
- climate change
- cell therapy
- dna binding
- electronic health record
- histone deacetylase
- chemotherapy induced