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 ß-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.
Subject(s)
Acetophenones/pharmacology , Benzopyrans/pharmacology , KCNQ1 Potassium Channel/agonists , Potassium Channels, Voltage-Gated/agonists , Xenopus Proteins/agonists , Acetophenones/chemical synthesis , Acetophenones/metabolism , Animals , Benzopyrans/chemical synthesis , Benzopyrans/metabolism , Binding Sites , Humans , KCNQ1 Potassium Channel/metabolism , Molecular Docking Simulation , Oocytes/drug effects , Protein Binding , Xenopus laevisABSTRACT
The cyclooctadepsipeptide PF1022A and its semisynthetic, commercial analogue emodepside show excellent anthelmintic properties. Bis-hydroxy PF1022 (PF1022H), a minor fermentative side-product represents an interesting precursor for new PF1022 related anthelmintics. We report herein two complementary routes which allow a highly efficient conversion of PF1022A to a regioisomeric mixture consisting mainly of the bis-para isomer PF1022H and the meta-para analogue.
Subject(s)
Anthelmintics/chemical synthesis , Depsipeptides/chemical synthesis , Peptides, Cyclic/chemical synthesis , Anthelmintics/chemistry , Depsipeptides/chemistry , Oxidation-Reduction , Peptides, Cyclic/chemistry , StereoisomerismABSTRACT
Phenyllactic acids are found in numerous natural products as well as in active substances used in medicine or plant protection. Enantiomerically pure phenyllactic acids are available by transition-metal-catalyzed hydrogenations or chemoenzymatic reductions of the corresponding 3-aryl-2-oxopropanoic acids. We show here that d-lactate dehydrogenase from Staphylococcus epidermidis reduces a broad spectrum of 2-oxo acids, which are difficult substrates for transition-metal-catalyzed reactions, with excellent enantioselectivities in a simple experimental setup.
Subject(s)
Lactate Dehydrogenases/chemistry , Propionates/chemistry , Staphylococcus/chemistry , Transition Elements/chemistry , Catalysis , Hydrogenation , Lactate Dehydrogenases/metabolism , Molecular Structure , StereoisomerismABSTRACT
Faced with the need to find new drugs for all kinds of diseases, science sees that Nature offers numerous classes of compounds showing an impressively high biological potential. Among those are the cyclodepsipeptides, hybrid structures composed of amino and hydroxy acids. In the past decades numerous cyclodepsipeptides have been isolated and their potential as drugs has been studied extensively. For several cyclodepsipeptides total syntheses both in solution and on solid-phase have been established, allowing the production of combinatorial libraries. In addition, the biosynthesis of specific cyclodepsipeptides has been elucidated and used for the chemoenzymatic preparation of nonnatural analogues. This review summarizes the recent literature on cyclic tetra- to decadepsipeptides, composed exclusively of α-amino- and α-hydroxy acids.
