%0 Journal Article
%T Backbone-Determined Antiarrhythmic Structure-Activity Relationships for a Mirror Image, Oligomeric Depsipeptide Natural Product.
%A Thorpe MP
%A Blackwell DJ
%A Knollmann BC
%A Johnston JN
%J J Med Chem
%V 67
%N 14
%D 2024 Jul 25
%M 38958200
%F 8.039
%R 10.1021/acs.jmedchem.4c00923
%X Cyclic oligomeric depsipeptides (COD) are a structural class within naturally occurring compounds with a wide range of biological activity. Verticilide is a COD (24-membered ring) that was identified by its inhibition of insect ryanodine receptor (RyR). We have since found that the enantiomer of verticilide (ent-verticilide, 1) is a potent inhibitor of mammalian RyR2, a cardiac calcium channel, and therefore a potential antiarrhythmic agent. Oddly, nat-verticilide does not inhibit RyR2. To further develop ent-verticilide as an antiarrhythmic, we explored potential SAR through systematic modification of the ester's functionality to both N-H and N-Me amides. The syntheses of these ent-verticilide-inspired analogs are detailed using a monomer-based platform enabled by enantioselective catalysis. Two analogs among 23 exhibited measurable reduction of calcium sparks in a functional assay of RyR2 activity. These findings illustrate the value of natural product-inspired therapeutic development, but the less-studied approach where the non-natural enantiomeric series harbors important SAR.