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.