Li Wenyuan, Paladugu Srinivas R, Liles Jordan P, Karthikeyan Manju, Chase Kevin, Raghuraman Shrinivasan, Sigman Matthew S, Looper Ryan E
Department of Chemistry, University of Utah, Salt Lake City, UT, 84102, USA.
School of Biological Sciences, University of Utah, Salt Lake City, UT, 84102, USA.
Chembiochem. 2025 May 27;26(10):e202500170. doi: 10.1002/cbic.202500170. Epub 2025 Apr 4.
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.
泽特克毒素AB是双胍离子毒素中唯一的大环成员，也是唯一被报道比母体（+）-石房蛤毒素更具效力的成员。由于天然材料稀缺且毒素本身的具体结构缺乏共识，很难找到这种卓越效力的原理。本文报道了一种策略，利用分子内迈克尔加成反应构建连接石房蛤毒素核心的大环，模仿泽特克毒素AB的推测结构。有趣的是，这些类似物在C12处不会形成水合物。实验和计算研究表明，大环框架会使水合物不稳定，这让人怀疑泽特克毒素中是否存在大环结构。利用基于钙成像的星座药理学进行的初步活性筛选表明，尽管缺乏C12水合酮，但几种类似物仍具有与（+）-石房蛤毒素相似的强大药理活性。
