Open AccessThe cyanobacterial metabolite nocuolin a is a natural oxadiazine that triggers apoptosis in human cancer cells
Author(s) -
Kateřina Voráčová,
Jan Hájek,
Jan Mareš,
Petra Urajová,
Marek Kuzma,
José Cheel,
Andreas Villunger,
Alexandra Kapuscik,
Marcel B. Bally,
Petr Novák,
Martin Kabeláč,
Gerhard Krumschnabel,
Martin Lukeš,
Ludmila N. Voloshko,
J. Kopecký,
Pavel Hrouzek
Publication year - 2017
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0172850
Subject(s) - apoptosis , metabolite , cancer cell , cell culture , biology , chemistry , programmed cell death , stereochemistry , cancer , biochemistry , genetics
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.