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

Abstract

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.

• Authors: Kateřina Voráčová, Jan Hájek, Jan Mareš, Petra Urajová, Marek Kuzma, José Cheel, Andreas Villunger, Alexandra Kapuscik, Marcel Bally, Petr Novák, Martin Kabeláč, Gerhard Krumschnabel, Martin Lukeš, Ludmila Voloshko, Jiří Kopecký, Pavel Hrouzek
• Journal: PloS one (PLoS One) Vol. 12 Issue 3 Pg. e0172850 ( 2017) ISSN: 1932-6203 [Electronic] United States
• PMID: 28253280 (Publication Type: Journal Article)

Chemical References

• Oxazines
• nocuolin A

Topics

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