title: Development and characterization of proteasome inhibitors.
abstract: Although many proteasome inhibitors have been either synthesized or identified from natural sources, the development of more sophisticated, selective proteasome inhibitors is important for a detailed understanding of proteasome function. We have found that antitumor natural product epoxomicin and eponemycin, both of which are linear peptides containing a alpha,beta-epoxyketone pharmacophore, target proteasome for their antitumor activity. Structural studies of the proteasome-epoxomicin complex revealed that the unique specificity of the natural product toward proteasome is due to the alpha,beta-epoxyketone pharmacophore, which forms an unusual six-membered morpholino ring with the amino terminal catalytic Thr-1 of the 20S proteasome. Thus, we believe that a facile synthetic approach for alpha,beta-epoxyketone linear peptides provides a unique opportunity to develop proteasome inhibitors with novel activities. In this chapter, we discuss the detailed synthetic procedure of the alpha',beta'-epoxyketone natural product epoxomicin and its derivatives.
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, Yale University, New Haven, Connecticut, USA.
authors.forename: Kyung
authors.initials: K
authors.lastname: Bo Kim
authors.forename: Fabiana N
authors.initials: FN
authors.lastname: Fonseca
authors.forename: Craig M
authors.initials: CM
authors.lastname: Crews
mesh_terms: D002851:Chromatography, High Pressure Liquid; D015195:Drug Design; D007700:Kinetics; D009842:Oligopeptides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D011480:Protease Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D009842:Oligopeptides; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex; C078846:epoxomicin