Total synthesis of the potent proteasome inhibitor epoxomicin: a useful tool for understanding proteasome biology.
Epoxomicin (1), a peptide alpha',beta'-epoxyketone isolated from the actinomycete strain No.Q996-17, possesses potent in vivo anti-tumor and anti-inflammatory activities. In this paper, we report the first syntheses of epoxomicin, [3H]-epoxomicin, and a biotinylated epoxomicin analog as well as the absolute configuration of the epoxide stereocenter. The natural product and derivatives have permitted the first identification of the proteasome as the specific cellular target of epoxomicin.
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Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520-8103, USA.
Kim
K B
KB
Elofsson
M
M
Meng
L
L
Auth
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H
Kwok
B H
BH
Crews
C M
CM
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000494:pharmacology; D019921:Biotinylation; D003546:Cysteine Endopeptidases / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D009097:Multienzyme Complexes / Q000187:drug effects / Q000378:metabolism*; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D011955:Receptors, Drug / Q000302:isolation & purification; D014407:Tumor Cells, Cultured
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D009842:Oligopeptides; D011955:Receptors, Drug; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C078846:epoxomicin