title: Apratoxin H and apratoxin A sulfoxide from the Red Sea cyanobacterium Moorea producens.
abstract: Cultivation of the marine cyanobacterium Moorea producens, collected from the Nabq Mangroves in the Gulf of Aqaba (Red Sea), led to the isolation of new apratoxin analogues apratoxin H (1) and apratoxin A sulfoxide (2), together with the known apratoxins A-C, lyngbyabellin B, and hectochlorin. The absolute configuration of these new potent cytotoxins was determined by chemical degradation, MS, NMR, and CD spectroscopy. Apratoxin H (1) contains pipecolic acid in place of the proline residue present in apratoxin A, expanding the known suite of naturally occurring analogues that display amino acid substitutions within the final module of the apratoxin biosynthetic pathway. The oxidation site of apratoxin A sulfoxide (2) was deduced from MS fragmentation patterns and IR data, and 2 could not be generated experimentally by oxidation of apratoxin A. The cytotoxicity of 1 and 2 to human NCI-H460 lung cancer cells (IC₅₀ = 3.4 and 89.9 nM, respectively) provides further insight into the structure-activity relationships in the apratoxin series. Phylogenetic analysis of the apratoxin-producing cyanobacterial strains belonging to the genus Moorea, coupled with the recently annotated apratoxin biosynthetic pathway, supports the notion that apratoxin production and structural diversity may be specific to their geographical niche.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University , Corvallis, Oregon 97331, United States.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Thornburg
authors.forename: Elise S
authors.initials: ES
authors.lastname: Cowley
authors.forename: Justyna
authors.initials: J
authors.lastname: Sikorska
authors.forename: Lamiaa A
authors.initials: LA
authors.lastname: Shaala
authors.forename: Jane E
authors.initials: JE
authors.lastname: Ishmael
authors.forename: Diaa T A
authors.initials: DT
authors.lastname: Youssef
authors.forename: Kerry L
authors.initials: KL
authors.lastname: McPhail
mesh_terms: D000458:Cyanobacteria / Q000737:chemistry*; D003603:Cytotoxins / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D047630:Depsipeptides / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D019156:Indian Ocean; D020128:Inhibitory Concentration 50; D007783:Lactones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D008235:Lyngbya Toxins / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D008386:Marine Biology; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010875:Pipecolic Acids / Q000737:chemistry; D012451:Safrole / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D013844:Thiazoles / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*
chemical_list: D003603:Cytotoxins; D047630:Depsipeptides; D007783:Lactones; D008235:Lyngbya Toxins; D010875:Pipecolic Acids; D013844:Thiazoles; C442201:apratoxin A; C584994:apratoxin A sulfoxide; C454807:hectochlorin; C416586:lyngbyabellin B; C560796:lyngbyabellin C; D012451:Safrole; C005746:sulfoxide
references.citation: J Nat Prod. 1998 Oct;61(10):1248-51
references.pmid: 9784161
references.citation: ACS Med Chem Lett. 2011 Nov 10;2(11):861-865
references.pmid: 22081789
references.citation: J Antibiot (Tokyo). 1989 Dec;42(12):1768-74
references.pmid: 2621160
references.citation: Blood. 2003 Aug 15;102(4):1458-65
references.pmid: 12714494
references.citation: J Nat Prod. 2008 Dec;71(12):2060-3
references.pmid: 19007282
references.citation: Mol Pharmacol. 2009 Jul;76(1):91-104
references.pmid: 19403701
references.citation: J Am Chem Soc. 2006 Mar 22;128(11):3838-47
references.pmid: 16536560
references.citation: J Nat Prod. 2003 May;66(5):719-21
references.pmid: 12762818
references.citation: Chem Biol. 2000 Mar;7(3):211-24
references.pmid: 10712928
references.citation: Chembiochem. 2010 Jul 5;11(10):1458-66
references.pmid: 20512792
references.citation: Genome Res. 1999 Sep;9(9):868-77
references.pmid: 10508846
references.citation: J Nat Prod. 2007 Oct;70(10):1611-5
references.pmid: 17935298
references.citation: Appl Environ Microbiol. 2005 Dec;71(12):7724-36
references.pmid: 16332745
references.citation: J Nat Prod. 2000 Oct;63(10):1440-3
references.pmid: 11076574
references.citation: Appl Environ Microbiol. 2006 Sep;72(9):5734-41
references.pmid: 16957188
references.citation: J Nat Prod. 2008 Jun;71(6):1099-103
references.pmid: 18444683
references.citation: J Org Chem. 2010 Dec 3;75(23):8012-23
references.pmid: 21047144
references.citation: BMC Biotechnol. 2002 Sep 23;2:17
references.pmid: 12270067
references.citation: J Nat Prod. 2011 Aug 26;74(8):1677-85
references.pmid: 21806012
references.citation: J Nat Prod. 2000 Jul;63(7):956-9
references.pmid: 10924173
references.citation: Mol Biol Evol. 2008 Jul;25(7):1253-6
references.pmid: 18397919
references.citation: Anal Chem. 2009 Jun 1;81(11):4200-9
references.pmid: 19413302
references.citation: J Am Soc Mass Spectrom. 1999 Apr;10(4):360-3
references.pmid: 10197354
references.citation: J Nat Prod. 2002 Jun;65(6):866-71
references.pmid: 12088429
references.citation: J Org Chem. 1996 Sep 6;61(18):6302-6304
references.pmid: 11667471
references.citation: Bioinformatics. 2001 Aug;17(8):754-5
references.pmid: 11524383
references.citation: J Am Chem Soc. 2001 Jun 13;123(23):5418-23
references.pmid: 11389621
references.citation: J Nat Prod. 1996 Jun;59(6):581-6
references.pmid: 8786364
references.citation: J Nat Prod. 2007 Jun;70(6):936-40
references.pmid: 17497807
references.citation: Syst Biol. 2003 Oct;52(5):696-704
references.pmid: 14530136
references.citation: PLoS One. 2013 Jun 06;8(6):e65250
references.pmid: 23762328
references.citation: Int J Syst Evol Microbiol. 2012 May;62(Pt 5):1171-1178
references.pmid: 21724952
references.citation: J Nat Prod. 2008 Jun;71(6):1113-6
references.pmid: 18461997
references.citation: Chemistry. 2006 Oct 10;12(29):7615-26
references.pmid: 16832801
references.citation: PLoS One. 2011 Apr 12;6(4):e18565
references.pmid: 21533272
references.citation: Chemistry. 2013 May 17;19(21):6774-84
references.pmid: 23536467
references.citation: Nat Prod Rep. 2012 Apr;29(4):449-56
references.pmid: 22334030
references.citation: Bioorg Med Chem. 2002 Jun;10(6):1973-8
references.pmid: 11937357