{Reference Type}: Journal Article
{Title}: Backbone-Determined Antiarrhythmic Structure-Activity Relationships for a Mirror Image, Oligomeric Depsipeptide Natural Product.
{Author}: Thorpe MP;Blackwell DJ;Knollmann BC;Johnston JN;
{Journal}: J Med Chem
{Volume}: 67
{Issue}: 14
{Year}: 2024 Jul 25
{Factor}: 8.039
{DOI}: 10.1021/acs.jmedchem.4c00923
{Abstract}: 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.