Fang Runting, Jiao Yang, Xia Tianrun, Liu Jiaqi, Luo Tuoping
Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
Key Laboratory of Bioorganic Chemistry and Molecular Engineering, Ministry of Education and Beijing National Laboratory for Molecular Science, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
JACS Au. 2025 Aug 26;5(9):4178-4183. doi: 10.1021/jacsau.5c01028. eCollection 2025 Sep 22.
(+)-Saxitoxin, a potent and reversible blocker of voltage-gated sodium channels, has attracted considerable interests as a scaffold for the development of novel analogs. Here, we report the design and synthesis of a tetracyclic analogue featuring an additional -fused five-membered ring (C5-C6), constructed via a novel photoinduced radical cycloaddition reaction. This transformation efficiently established the quaternary carbon center at C5, which is difficult to access by conventional methods. Although the IC values of two analogues against hNa1.4 showed a significant decrease in potency, this work introduces a new chemotype of saxitoxin, offering a foundation for future optimization efforts.
（+）-石房蛤毒素是一种强效且可逆的电压门控钠通道阻滞剂，作为新型类似物开发的骨架已引起了相当大的关注。在此，我们报告了一种四环类似物的设计与合成，该类似物具有一个额外的稠合五元环（C5-C6），通过一种新型光诱导自由基环加成反应构建而成。这种转化有效地在C5处建立了季碳中心，这是传统方法难以实现的。尽管两种类似物对hNa1.4的IC值显示效力显著降低，但这项工作引入了一种新的石房蛤毒素化学类型，为未来的优化工作提供了基础。
