Synthesis of portimines reveals the basis of their anti-cancer activity

Junchen Tang, Weichao Li, Tzu-Yuan Chiu, Francisco Martínez-Peña, Zengwei Luo, Christine T. Chong, Qijia Wei, Nathalia Gazaniga, Thomas J. West, Yi Yang See, Luke L. Lairson (), Christopher G. Parker () and Phil S. Baran ()
Additional contact information
Junchen Tang: Scripps Research
Weichao Li: Scripps Research
Tzu-Yuan Chiu: Scripps Research
Francisco Martínez-Peña: Scripps Research
Zengwei Luo: Scripps Research
Christine T. Chong: Scripps Research
Qijia Wei: Scripps Research
Nathalia Gazaniga: Scripps Research
Thomas J. West: Scripps Research
Yi Yang See: Scripps Research
Luke L. Lairson: Scripps Research
Christopher G. Parker: Scripps Research
Phil S. Baran: Scripps Research

Nature, 2023, vol. 622, issue 7983, 507-513

Abstract: Abstract Marine-derived cyclic imine toxins, portimine A and portimine B, have attracted attention because of their chemical structure and notable anti-cancer therapeutic potential1–4. 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 synthesis5,6 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.

Date: 2023
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DOI: 10.1038/s41586-023-06535-1

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