title: Cystargolides, 20S Proteasome Inhibitors Isolated from Kitasatospora cystarginea.
abstract: Two novel β-lactone-containing natural products, cystargolides A (1) and B (2), were isolated from the actinomycete Kitasatospora cystarginea. The production of these two natural products was highlighted using a methodology associating liquid chromatography-high-resolution mass spectrometry (LC-HRMS) analysis and the statistical analysis tool principal component analysis (PCA). Their structures were elucidated by interpretation of NMR experiments and tandem mass spectrometry. The absolute configurations of the amino acid residues were determined using Marfey's method, and the relative configurations of the β-lactone substituents were determined on the basis of the vicinal (3)J(HH) coupling value. Due to the presence of the β-lactone, 1 and 2 were evaluated for their ability to inhibit the human 20S proteasome. 1 and 2 both inhibited the 20S proteasome in vitro with IC50 values of 0.35 and 0.93 μM, respectively.
authors.affiliation: †Department of Chemistry, University of Prince Edward Island, 550 University Avenue, Charlottetown, PE, Canada C1A 4P3.
authors.forename: Krista A
authors.initials: KA
authors.lastname: Gill
authors.affiliation: †Department of Chemistry, University of Prince Edward Island, 550 University Avenue, Charlottetown, PE, Canada C1A 4P3.|‡Nautilus Biosciences Canada Inc., DRC 550 University Avenue, Charlottetown, PE, Canada C1A 4P3.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Berrué
authors.affiliation: §Department of Biomedical Sciences, Atlantic Veterinary College, 550 University Avenue, Charlottetown, PE, Canada C1A 4P3.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Arens
authors.affiliation: ‡Nautilus Biosciences Canada Inc., DRC 550 University Avenue, Charlottetown, PE, Canada C1A 4P3.
authors.forename: Gavin
authors.initials: G
authors.lastname: Carr
authors.affiliation: †Department of Chemistry, University of Prince Edward Island, 550 University Avenue, Charlottetown, PE, Canada C1A 4P3.|‡Nautilus Biosciences Canada Inc., DRC 550 University Avenue, Charlottetown, PE, Canada C1A 4P3.|§Department of Biomedical Sciences, Atlantic Veterinary College, 550 University Avenue, Charlottetown, PE, Canada C1A 4P3.
authors.forename: Russell G
authors.initials: RG
authors.lastname: Kerr
mesh_terms: D039903:Actinobacteria / Q000737:chemistry*; D001688:Biological Products / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D004151:Dipeptides / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D006801:Humans; D007783:Lactones / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects*; D061988:Proteasome Inhibitors / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*
chemical_list: D001688:Biological Products; D004151:Dipeptides; D007783:Lactones; D061988:Proteasome Inhibitors; C000600874:cystargolide A; C000600875:cystargolide B; D046988:Proteasome Endopeptidase Complex