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PLoS One. 2017 Mar 2;12(3):e0172850. doi: 10.1371/journal.pone.0172850. eCollection 2017.

The cyanobacterial metabolite nocuolin a is a natural oxadiazine that triggers apoptosis in human cancer cells.

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Centre Algatech, Institute of Microbiology, The Czech Academy of Sciences (CAS) v.v.i., Třeboň, Czech Republic.
University of South Bohemia, Faculty of Science, České Budějovice, Czech Republic.
Biology Centre (CAS) v.v.i., Institute of Hydrobiology, České Budějovice, Czech Republic.
Centre for Phycology, Institute of Botany (CAS) v.v.i., Czech Republic.
Laboratory of Molecular Structure Characterization, Institute of Microbiology (CAS), Prague, Czech Republic.
Medical University Innsbruck, Division of Developmental Immunology, Biocenter Innsbruck, Innsbruck, Austria.
Tyrolean Cancer Research Institute, Innsbruck, Austria.
British Columbia Cancer Agency, Department of Experimental Therapeutics, Vancouver, BC Canada.
Saint Petersburg State University, St. Petersburg, Russia.


Oxadiazines are heterocyclic compounds containing N-N-O or N-N-C-O system within a six membered ring. These structures have been up to now exclusively prepared via organic synthesis. Here, we report the discovery of a natural oxadiazine nocuolin A (NoA) that has a unique structure based on 1,2,3-oxadiazine. We have identified this compound in three independent cyanobacterial strains of genera Nostoc, Nodularia, and Anabaena and recognized the putative gene clusters for NoA biosynthesis in their genomes. Its structure was characterized using a combination of NMR, HRMS and FTIR methods. The compound was first isolated as a positive hit during screening for apoptotic inducers in crude cyanobacterial extracts. We demonstrated that NoA-induced cell death has attributes of caspase-dependent apoptosis. Moreover, NoA exhibits a potent anti-proliferative activity (0.7-4.5 μM) against several human cancer lines, with p53-mutated cell lines being even more sensitive. Since cancers bearing p53 mutations are resistant to several conventional anti-cancer drugs, NoA may offer a new scaffold for the development of drugs that have the potential to target tumor cells independent of their p53 status. As no analogous type of compound was previously described in the nature, NoA establishes a novel class of bioactive secondary metabolites.

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