Synthesis of Portimines Reveals the Basis of Their Anti-cancer Activity

Overview

Journal Nature

Specialty Science

Date 2023 Sep 21

PMID 37730997

Authors

Junchen Tang

Weichao Li

Tzu-Yuan Chiu

Francisco Martinez-Pena

Zengwei Luo

Christine T Chong

Qijia Wei

Nathalia Gazaniga

Thomas J West

Yi Yang See

Luke L Lairson

Christopher G Parker

Phil S Baran

Affiliations

Soon will be listed here.

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. 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.

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References

Stivala C, Benoit E, Araoz R, Servent D, Novikov A, Molgo J . Synthesis and biology of cyclic imine toxins, an emerging class of potent, globally distributed marine toxins. Nat Prod Rep. 2014; 32(3):411-35. PMC: 4344380. DOI: 10.1039/c4np00089g. View

Molgo J, Marchot P, Araoz R, Benoit E, Iorga B, Zakarian A . Cyclic imine toxins from dinoflagellates: a growing family of potent antagonists of the nicotinic acetylcholine receptors. J Neurochem. 2017; 142 Suppl 2:41-51. PMC: 5550345. DOI: 10.1111/jnc.13995. View

Cuddihy S, Drake S, Harwood D, Selwood A, McNabb P, Hampton M . The marine cytotoxin portimine is a potent and selective inducer of apoptosis. Apoptosis. 2016; 21(12):1447-1452. DOI: 10.1007/s10495-016-1302-x. View

Jorgensen L, McKerrall S, Kuttruff C, Ungeheuer F, Felding J, Baran P . 14-step synthesis of (+)-ingenol from (+)-3-carene. Science. 2013; 341(6148):878-82. DOI: 10.1126/science.1241606. View

Kanda Y, Nakamura H, Umemiya S, Puthukanoori R, Appala V, Gaddamanugu G . Two-Phase Synthesis of Taxol. J Am Chem Soc. 2020; 142(23):10526-10533. PMC: 8349513. DOI: 10.1021/jacs.0c03592. View

Munday R, Selwood A, Rhodes L . Acute toxicity of pinnatoxins E, F and G to mice. Toxicon. 2012; 60(6):995-9. DOI: 10.1016/j.toxicon.2012.07.002. View

Munday R, Quilliam M, LeBlanc P, Lewis N, Gallant P, Sperker S . Investigations into the toxicology of spirolides, a group of marine phycotoxins. Toxins (Basel). 2012; 4(1):1-14. PMC: 3277094. DOI: 10.3390/toxins4010001. View

Munday R, Towers N, MacKenzie L, Beuzenberg V, Holland P, Miles C . Acute toxicity of gymnodimine to mice. Toxicon. 2004; 44(2):173-8. DOI: 10.1016/j.toxicon.2004.05.017. View

Fribley A, Xi Y, Makris C, Alves-de-Souza C, York R, Tomas C . Identification of Portimine B, a New Cell Permeable Spiroimine That Induces Apoptosis in Oral Squamous Cell Carcinoma. ACS Med Chem Lett. 2019; 10(2):175-179. PMC: 6378672. DOI: 10.1021/acsmedchemlett.8b00473. View

10.

Hermawan I, Higa M, Hutabarat P, Fujiwara T, Akiyama K, Kanamoto A . Kabirimine, a New Cyclic Imine from an Okinawan Dinoflagellate. Mar Drugs. 2019; 17(6). PMC: 6627061. DOI: 10.3390/md17060353. View

11.

MacKinnon S, Cembella A, Burton I, Lewis N, LeBlanc P, Walter J . Biosynthesis of 13-desmethyl spirolide C by the dinoflagellate Alexandrium ostenfeldii. J Org Chem. 2006; 71(23):8724-31. DOI: 10.1021/jo0608873. View

12.

Kellmann R, Stuken A, Orr R, Svendsen H, Jakobsen K . Biosynthesis and molecular genetics of polyketides in marine dinoflagellates. Mar Drugs. 2010; 8(4):1011-48. PMC: 2866473. DOI: 10.3390/md8041011. View

13.

Wagoner R, Satake M, Wright J . Polyketide biosynthesis in dinoflagellates: what makes it different?. Nat Prod Rep. 2014; 31(9):1101-37. DOI: 10.1039/c4np00016a. View

14.

Stivala C, Zakarian A . Total synthesis of (+)-pinnatoxin A. J Am Chem Soc. 2008; 130(12):3774-6. DOI: 10.1021/ja800435j. View

15.

Araoz R, Servent D, Molgo J, Iorga B, Fruchart-Gaillard C, Benoit E . Total synthesis of pinnatoxins A and G and revision of the mode of action of pinnatoxin A. J Am Chem Soc. 2011; 133(27):10499-511. PMC: 3365589. DOI: 10.1021/ja201254c. View

16.

Kong K, Moussa Z, Lee C, Romo D . Total synthesis of the spirocyclic imine marine toxin (-)-gymnodimine and an unnatural C4-epimer. J Am Chem Soc. 2011; 133(49):19844-56. PMC: 3256008. DOI: 10.1021/ja207385y. View

17.

Ding X, Aitken H, Pearl E, Furkert D, Brimble M . Synthesis of the C4-C16 Polyketide Fragment of Portimines A and B. J Org Chem. 2021; 86(18):12840-12850. DOI: 10.1021/acs.joc.1c01463. View

18.

Li L, El Khoury A, Clement B, Wu C, Harran P . Asymmetric Organocatalysis Enables Rapid Assembly of Portimine Precursor Chains. Org Lett. 2022; 24(14):2607-2612. DOI: 10.1021/acs.orglett.2c00556. View

19.

Huang Y, Iwama T, Rawal V . Design and development of highly effective Lewis acid catalysts for enantioselective Diels-Alder reactions. J Am Chem Soc. 2002; 124(21):5950-1. DOI: 10.1021/ja026088t. View

20.

Hillenbrand J, Leutzsch M, Yiannakas E, Gordon C, Wille C, Nothling N . "Canopy Catalysts" for Alkyne Metathesis: Molybdenum Alkylidyne Complexes with a Tripodal Ligand Framework. J Am Chem Soc. 2020; 142(25):11279-11294. PMC: 7322728. DOI: 10.1021/jacs.0c04742. View