Cinnabaramides A-G: analogues of lactacystin and salinosporamide from a terrestrial streptomycete.
The cinnabaramides A-G (1-7) were isolated from a terrestrial strain of Streptomyces as potent and selective inhibitors of the human 20S proteasome. Their chemical and biological properties resemble those of salinosporamide A, a recently identified lead compound from an obligate marine actinomycete, which is currently under development as an anticancer agent. Cinnabaramides F and G (6, 7) combine essential structural features of salinosporamide A and lactacystin and show about equal potency in vitro, with IC50 values in the 1 nM range. The properties and phylogenetic position of the producer organism, the production and isolation of compounds 1-7, their structure elucidation by MS and NMR, and their biological activities are reported. Additionally, an X-ray crystal structure was obtained from cinnabaramide A (1).
Stadler
Marc
M
InterMed Discovery GmbH (IMD), Otto-Hahn-Strasse 15, D-44227 Dortmund, Germany. marc.stadler@t-online.de
Bitzer
Jens
J
Mayer-Bartschmid
Anke
A
Müller
Hartwig
H
Benet-Buchholz
Jordi
J
Gantner
Florian
F
Tichy
Hans-Volker
HV
Reinemer
Peter
P
Bacon
Kevin B
KB
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D018360:Crystallography, X-Ray; D006801:Humans; D007783:Lactones / Q000097:blood / Q000302:isolation & purification / Q000494:pharmacology; D008968:Molecular Conformation; D015394:Molecular Structure; D061988:Proteasome Inhibitors; D011758:Pyrroles / Q000097:blood / Q000302:isolation & purification / Q000494:pharmacology; D013302:Streptomyces / Q000737:chemistry*
D007783:Lactones; D061988:Proteasome Inhibitors; D011758:Pyrroles; C067713:lactacystin; C475865:marizomib; D000111:Acetylcysteine