| dc.description.abstract | Cyclooligomeric depsipeptides display a diverse range of biological activity and hold strong promise as potential therapeutics. However, the development of drug molecules in this larger size regime is still far less explored than traditional small molecules. The Johnston lab previously reported the synthesis of the fungal cyclic oligomeric natural product (-)-nat-verticilide as well as its enantiomer, (+)-ent-verticilide, to determine their activity against mammalian RyR2, a cardiac calcium ion channel. While the natural product had no effect, the non-natural enantiomer significantly reduced RyR2-mediated spontaneous calcium release, making it a potential therapeutic for RyR2 related heart diseases. This dissertation describes a reinvestigation into the synthesis of cyclooligomeric depsipeptides by macrocyclooligomerization (MCO) reactions, and progress towards the development of a new class of antiarrhythmic agents using the hit compound ent-verticilide. In the reinvestigation of the MCO of a tetradepsipeptide, a paradox was uncovered in which the MCO can produce “impossible” ring sizes: a 12-atom chain produced the expected 24-membered ring, alongside unexpected 18- and 30-membered cyclic oligomeric depsipeptides (CODs). Recharacterization and reassignment of two macrocycles, updated yields, isothermal titration calorimetry (ITC) data, new purification protocols, and initial mechanistic analysis are detailed. Following this discovery, new synthetic routes to ent-verticilide cyclodepsipeptide analogues were developed and utilized in a structure-based design approach to help clarify the interaction of ent-verticilide with RyR2. This approach led to several additional potent RyR2 modulators, as well as provided insight into the pharmacophore of ent-verticilide. The SAR studies described within aided the development and synthesis of fluorescent and photo-affinity labeling probes to work towards defining the mechanism of action of ent-verticilide to treat cardiac arrythmias. | |
