Macrocycles of Saxitoxin: Insights into the Structure of Zetekitoxin AB.

Zeteketoxin AB is the only macrocyclic member of the bis-guanidinium ion toxins, and the only member reported to be more potent than the parent (+)-saxitoxin. A rationale for this exquisite potency remains difficult to develop due to the scarcity of natural material and a lack of consensus around the specific structure of the toxin itself. A strategy is reported, leveraging an intramolecular Michael addition to forge macrocycles bridging the saxitoxin core, mimicking the proposed structure of zetekitoxin AB. Intriguingly, these analogs do not form a hydrate at C12. Experimental and computational studies suggest that a macrocyclic framework destabilizes the hydrate, casting doubt on the presence of a macrocycle in zetekitoxin. Preliminary activity screening utilizing calcium imaging-based constellation pharmacology demonstrates several analogs to have potent pharmacological activity similar to (+)-saxitoxin despite the lack of the C12 hydrated ketone.