近日，美国斯克里普斯研究所Phil S. Baran团队研究了石蛤毒素及相关天然产物的可扩展全合成。这一研究成果发表在2025年8月26日出版的《自然》杂志上。

石蛤毒素（STX, 1）是一种从贝类中提取的强效神经毒素，于1957年首次分离出来，由于其与电压门控钠通道相互作用而具有巨大的药用潜力，而电压门控钠通道普遍存在于中枢和外周神经系统的所有可兴奋细胞中。迄今为止，已经公布了数百项针对这一目的的综合研究，然而，一种完全模块化和可扩展的家庭方法仍然存在。

因此，研究组展示了如何将自由基反合成、生物催化和C-H官能化逻辑结合起来解决这一问题，从而在不到10步的时间内实现对STX家族的可扩展方法，包括首次完全合成新氧毒素（neoSTX, 4），这是一种羟基化的天然STX类似物，此前已应用在临床研究中。该合成的模块化特性使人们能够获得以前无法获得的各种类似物，现在已经通过电生理分析对生物活性进行了评估。

附：英文原文

Title: Scalable total synthesis of saxitoxin and related natural products

Author: Guo, Yinliang, Li, Yiheng, Chen, Sihan, Wu, Yige, Poll, Oscar, Ren, Zhouyang, Liu, Zhonglin, Vlkolinsky, Roman, Bajo, Michal, Prier, Christopher K., Xiao, Kai-Jiong, Cravatt, Benjamin F., Roberto, Marisa, Baran, Phil S.

Issue&Volume: 2025-08-26

Abstract: Saxitoxin (STX, 1), a potent neurotoxin from shellfish, first isolated in 19571, offers immense pharmaceutical potential due to its interaction with voltage-gated sodium channels2, that are ubiquitously present in all excitable cells of the central and periphperal nervous system3. Hundreds of synthetic studies towards this end have been disclosed thus far, yet, a fully modular and scalable approach to the family remains elusive4-12. Thus, here we show how a tactical combination of radical retrosynthesis, biocatalysis, and C–H functionalization logic can be combined to solve this problem resulting in a scalable approach to the STX family in less than 10 steps including the first total synthesis of neosaxitoxin (neoSTX, 4), a hydroxylated naturally occurring STX analog previously under clinical investigation13. The modular nature of the synthesis enables access to diverse analogs, that were previously inaccessible, and now have been evaluated through electrophysiological assays for biological activity.

DOI: 10.1038/s41586-025-09551-5

Source: https://www.nature.com/articles/s41586-025-09551-5