Backbone-Determined Antiarrhythmic Structure–Activity Relationships for a Mirror Image, Oligomeric Depsipeptide Natural Product

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.