title: Total synthesis of TMC-95A and -B via a new reaction leading to Z-enamides. Some preliminary findings as to SAR.
abstract: A full account of the total syntheses of proteasome inhibitors TMC-95A and -B is provided. A key feature of the syntheses involved installation of a cis-propenylamide moiety by a thermal rearrangement of an alpha-silylallyl amide. The scope and mechanism of the enamide-forming reaction are discussed. Also provided are some preliminary results from SAR studies. It was found that simplified analogues can retain the full potency of proteasome inhibition.
authors.affiliation: Laboratory for Bioorganic Chemistry, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10021, USA.
authors.forename: Songnian
authors.initials: S
authors.lastname: Lin
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Yang
authors.forename: Benjamin H B
authors.initials: BH
authors.lastname: Kwok
authors.forename: Michael
authors.initials: M
authors.lastname: Koldobskiy
authors.forename: Craig M
authors.initials: CM
authors.lastname: Crews
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Danishefsky
mesh_terms: D000577:Amides / Q000737:chemistry; D000818:Animals; D002417:Cattle; D003546:Cysteine Endopeptidases; D004912:Erythrocytes / Q000737:chemistry / Q000187:drug effects; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D010456:Peptides, Cyclic / Q000138:chemical synthesis*; D010880:Piperidines / Q000737:chemistry; D046988:Proteasome Endopeptidase Complex; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D009097:Multienzyme Complexes; D010456:Peptides, Cyclic; D010880:Piperidines; C408291:TMC-95A; C408292:TMC-95B; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex