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Macrocycles of Saxitoxin: Insights into the Structure of Zetekitoxin AB
Author(s) -
Li Wenyuan,
Paladugu Srinivas R.,
Liles Jordan P.,
Karthikeyan Manju,
Chase Kevin,
Raghuraman Shrinivasan,
Sigman Matthew S.,
Looper Ryan E.
Publication year - 2025
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.202500170
Subject(s) - saxitoxin , chemistry , foldamer , intramolecular force , combinatorial chemistry , stereochemistry , toxin , biochemistry
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.