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

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


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.

MeSH terms

  • Amino Acid Sequence
  • Apoptosis / drug effects*
  • Chromatography, Liquid
  • Cyanobacteria / chemistry*
  • HeLa Cells
  • Humans
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Molecular Structure
  • Multigene Family
  • Oxazines / chemistry
  • Oxazines / pharmacology*
  • Sequence Homology, Amino Acid
  • Spectroscopy, Fourier Transform Infrared


  • Oxazines
  • nocuolin A

Grants and funding

This study was supported by Czech Science Foundation projects No. P503/12/P614 and No. 14-18067S and by the Ministry of Education, Youth and Sports of the Czech Republic, National Programme of Sustainability I, ID: LO1416. J. Cheel was supported by the project ALGAIN (reg. nr. CZ.1.07/2.3.00/30.0059). Access to computing and storage facilities owned by parties and projects contributing to the National Grid Infrastructure MetaCentrum, provided under the programme "Projects of Large Infrastructure for Research, Development, and Innovations" (LM2010005), is greatly appreciated. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.