Organic Chemistry

A Scalable Total Synthesis of Portimine A and B Reveals the Basis of Their Potent and Selective Anti-cancer Activity

Authors

Abstract

Marine derived cyclic imine toxins, portimine A and B, have attracted extensive attention owing to their intriguing chemical structure and promising anti-cancer therapeutic potential. However, access to large quantities is currently unfeasible and the molecular mechanism behind their potent activity is unknown. To address this, a scalable 15-step total synthesis of portimines is presented, which benefits from the logic used in two-phase terpenoid synthesis along with unique tactics such as exploiting ring-chain tautomerization and skeletal reorganization to minimize protecting group chemistry through “self-protection”. Critically, 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. Finally, practical access to the portimines and analogs thereof simplified the development of photoaffinity analogs, which were used in chemical proteomic experiments to identify a primary target of portimine A as the 60S ribosomal export protein NMD3.

Content

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Supplementary material

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Supplementary Information
Experimental procedure, NMR spectra
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Table S6 and S7
Raw proteomics data