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.

British Columbia Cancer Agency Department of Experimental Therapeutics Vancouver BC Canada

Centre Algatech Institute of Microbiology The Czech Academy of Sciences v v i Czech Republic

Centre Algatech Institute of Microbiology The Czech Academy of Sciences v v i Institute of Hydrobiology České Budějovice Czech Republic

Centre Algatech Institute of Microbiology The Czech Academy of Sciences v v i Třeboň Czech Republic

Centre Algatech Institute of Microbiology The Czech Academy of Sciences v v i Třeboň Czech Republic University of South Bohemia Faculty of Science České Budějovice Czech Republic

Laboratory of Molecular Structure Characterization Institute of Microbiology Prague Czech Republic

Medical University Innsbruck Division of Developmental Immunology Biocenter Innsbruck Innsbruck Austria

Medical University Innsbruck Division of Developmental Immunology Biocenter Innsbruck Innsbruck Austria Tyrolean Cancer Research Institute Innsbruck Austria

Saint Petersburg State University St Petersburg Russia

University of South Bohemia Faculty of Science České Budějovice Czech Republic

000      

00000naa a2200000 a 4500

001      

bmc17030997

003      

CZ-PrNML

005      

20171025122822.0

007      

ta

008      

171025s2017 xxu f 000 0|eng||

009      

AR

024    7_

$a 10.1371/journal.pone.0172850 $2 doi

035    __

$a (PubMed)28253280

040    __

$a ABA008 $b cze $d ABA008 $e AACR2

041    0_

$a eng

044    __

$a xxu

100    1_

$a Voráčová, Kateřina $u 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.

245    14

$a The cyanobacterial metabolite nocuolin a is a natural oxadiazine that triggers apoptosis in human cancer cells / $c K. Voráčová, J. Hájek, J. Mareš, P. Urajová, M. Kuzma, J. Cheel, A. Villunger, A. Kapuscik, M. Bally, P. Novák, M. Kabeláč, G. Krumschnabel, M. Lukeš, L. Voloshko, J. Kopecký, P. Hrouzek,

520    9_

$a 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.

650    _2

$a sekvence aminokyselin $7 D000595

650    _2

$a apoptóza $x účinky léků $7 D017209

650    _2

$a chromatografie kapalinová $7 D002853

650    _2

$a sinice $x chemie $7 D000458

650    _2

$a HeLa buňky $7 D006367

650    _2

$a lidé $7 D006801

650    _2

$a magnetická rezonanční spektroskopie $7 D009682

650    _2

$a hmotnostní spektrometrie $7 D013058

650    _2

$a molekulární struktura $7 D015394

650    _2

$a multigenová rodina $7 D005810

650    _2

$a oxaziny $x chemie $x farmakologie $7 D010078

650    _2

$a sekvenční homologie aminokyselin $7 D017386

650    _2

$a spektroskopie infračervená s Fourierovou transformací $7 D017550

655    _2

$a časopisecké články $7 D016428

700    1_

$a Hájek, Jan $u 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.

700    1_

$a Mareš, Jan $u 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.

700    1_

$a Urajová, Petra $u Centre Algatech, Institute of Microbiology, The Czech Academy of Sciences (CAS) v.v.i., Třeboň, Czech Republic.

700    1_

$a Kuzma, Marek $u Laboratory of Molecular Structure Characterization, Institute of Microbiology (CAS), Prague, Czech Republic.

700    1_

$a Cheel, José $u Centre Algatech, Institute of Microbiology, The Czech Academy of Sciences (CAS) v.v.i., Třeboň, Czech Republic.

700    1_

$a Villunger, Andreas $u Medical University Innsbruck, Division of Developmental Immunology, Biocenter Innsbruck, Innsbruck, Austria. Tyrolean Cancer Research Institute, Innsbruck, Austria.

700    1_

$a Kapuscik, Alexandra $u Centre Algatech, Institute of Microbiology, The Czech Academy of Sciences (CAS) v.v.i., Třeboň, Czech Republic.

700    1_

$a Bally, Marcel $u British Columbia Cancer Agency, Department of Experimental Therapeutics, Vancouver, BC Canada.

700    1_

$a Novák, Petr $u Laboratory of Molecular Structure Characterization, Institute of Microbiology (CAS), Prague, Czech Republic.

700    1_

$a Kabeláč, Martin $u University of South Bohemia, Faculty of Science, České Budějovice, Czech Republic.

700    1_

$a Krumschnabel, Gerhard $u Medical University Innsbruck, Division of Developmental Immunology, Biocenter Innsbruck, Innsbruck, Austria.

700    1_

$a Lukeš, Martin $u Centre Algatech, Institute of Microbiology, The Czech Academy of Sciences (CAS) v.v.i., Třeboň, Czech Republic.

700    1_

$a Voloshko, Ludmila $u Saint Petersburg State University, St. Petersburg, Russia.

700    1_

$a Kopecký, Jiří $u Centre Algatech, Institute of Microbiology, The Czech Academy of Sciences (CAS) v.v.i., Třeboň, Czech Republic.

700    1_

$a Hrouzek, Pavel $u 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.

773    0_

$w MED00180950 $t PloS one $x 1932-6203 $g Roč. 12, č. 3 (2017), s. e0172850

856    41

$u https://pubmed.ncbi.nlm.nih.gov/28253280 $y Pubmed

910    __

$a ABA008 $b sig $c sign $y a $z 0

990    __

$a 20171025 $b ABA008

991    __

$a 20171025122904 $b ABA008

999    __

$a ok $b bmc $g 1254590 $s 992024

BAS    __

$a 3

BAS    __

$a PreBMC

BMC    __

$a 2017 $b 12 $c 3 $d e0172850 $e 20170302 $i 1932-6203 $m PLoS One $n PLoS One $x MED00180950

LZP    __

$a Pubmed-20171025