title: Stereospecific total syntheses of proteasome inhibitors omuralide and lactacystin.
abstract: Omuralide, a transformation product of the microbial metabolite lactacystin, was the first molecule discovered as a specific inhibitor of the proteasome and is unique in that it specifically inhibits the proteolytic activity of the 20S subunit of the proteasome without inhibiting any other protease activities of the cell. The total syntheses of omuralide and (+)-lactacystin are reported. An important key intermediate is synthesized at an early stage, which allows analogues of these two natural products to be made readily.
authors.affiliation: Department of Chemistry, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, Illinois 60208-3113, United States.
authors.forename: Wenxin
authors.initials: W
authors.lastname: Gu
authors.forename: Richard B
authors.initials: RB
authors.lastname: Silverman
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000032:analysis / Q000138:chemical synthesis / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018360:Crystallography, X-Ray; D015853:Cysteine Proteinase Inhibitors / Q000032:analysis / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007783:Lactones / Q000032:analysis / Q000138:chemical synthesis* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D009369:Neoplasms / Q000188:drug therapy; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D013237:Stereoisomerism
chemical_list: D015853:Cysteine Proteinase Inhibitors; D007783:Lactones; D061988:Proteasome Inhibitors; C117645:omuralide; C067713:lactacystin; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine