1. Synthesis of portimines reveals the basis of their anti-cancer activity.
- Author
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Tang J, Li W, Chiu TY, Martínez-Peña F, Luo Z, Chong CT, Wei Q, Gazaniga N, West TJ, See YY, Lairson LL, Parker CG, and Baran PS
- Subjects
- Humans, Apoptosis drug effects, Cell Line, Tumor, Neoplasms drug therapy, Proteomics, Ribosomes metabolism, RNA-Binding Proteins metabolism, Structure-Activity Relationship, Chemistry Techniques, Synthetic, Imines chemical synthesis, Imines chemistry, Imines pharmacology, Spiro Compounds chemical synthesis, Spiro Compounds chemistry, Spiro Compounds pharmacology, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology
- Abstract
Marine-derived cyclic imine toxins, portimine A and portimine B, have attracted attention because of their chemical structure and notable anti-cancer therapeutic potential
1-4 . 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., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2023
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