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Cystargolides, 20S Proteasome Inhibitors Isolated from Kitasatospora cystarginea

Gill, Krista A., Berrué, Fabrice, Arens, Jennifer C., Carr, Gavin, Kerr, Russell G.
Journal of natural products 2015 v.78 no.4 pp. 822-826
Kitasatospora cystarginea, amino acids, humans, inhibitory concentration 50, nuclear magnetic resonance spectroscopy, principal component analysis, proteasome endopeptidase complex, proteasome inhibitors, tandem mass spectrometry
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 ³JHH 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.