Department of Chemistry, Scripps Research, La Jolla, CA, USA.
Nature. 2023 Oct;622(7983):507-513. doi: 10.1038/s41586-023-06535-1. Epub 2023 Sep 20.
Marine-derived cyclic imine toxins, portimine A and portimine B, have attracted attention because of their chemical structure and notable anti-cancer therapeutic potential. However, access to large quantities of these toxins is currently not feasible, and the molecular mechanism underlying their potent activity remains unknown until now. To address this, a scalable and concise synthesis of portimines is presented, which benefits from the logic used in the two-phase terpenoid synthesis along with other tactics such as exploiting ring-chain tautomerization and skeletal reorganization to minimize protecting group chemistry through self-protection. Notably, this total synthesis enabled a structural reassignment of portimine B and an in-depth functional evaluation of portimine A, revealing that it induces apoptosis selectively in human cancer cell lines with high potency and is efficacious in vivo in tumour-clearance models. Finally, practical access to the portimines and their analogues simplified the development of photoaffinity analogues, which were used in chemical proteomic experiments to identify a primary target of portimine A as the 60S ribosomal export protein NMD3.
海洋衍生的环状亚胺毒素，波替霉素 A 和波替霉素 B，因其化学结构和显著的抗癌治疗潜力而受到关注。然而，目前无法获得大量这些毒素，并且其强大活性的分子机制至今仍不清楚。为了解决这个问题，提出了一种可扩展且简洁的波替霉素合成方法，该方法得益于萜类化合物的两相合成中使用的逻辑，以及其他策略，例如利用环链互变异构和骨架重排来通过自保护最小化保护基化学。值得注意的是，这种全合成实现了波替霉素 B 的结构重新分配，并对波替霉素 A 进行了深入的功能评估，结果表明它以高选择性在人类癌细胞系中诱导细胞凋亡，并且在肿瘤清除模型中具有体内疗效。最后，对波替霉素及其类似物的实际获得简化了光亲和类似物的开发，这些类似物用于化学蛋白质组学实验中，以确定波替霉素 A 的主要靶标是 60S 核糖体出口蛋白 NMD3。
