title: Synthesis and activity of tyropeptin A derivatives as potent and selective inhibitors of mammalian 20S proteasome.
abstract: Tyropeptin A, a potent proteasome inhibitor, was isolated from the culture broth of Kitasatospora sp. MK993-dF2. We synthesized the derivatives of tyropeptin A to enhance its inhibitory potency. Among the synthesized derivatives, the most potent compound, TP-104, exhibited a 20-fold inhibitory potency enhancement for chymotrypsin-like activity of 20S proteasome compared to tyropeptin A. Additionally, TP-110 specifically inhibited the chymotrypsin-like activity, but did not inhibit the post-glutamyl-peptide hydrolyzing (PGPH) and the trypsin-like activities of 20S proteasome. In vitro TP-110 strongly inhibited the growth of various cell lines.
authors.affiliation: Numazu Bio-Medical Research Institute, Microbial Chemistry Research Center, Shizuoka 410-0301, Japan. imomose@bikaken.or.jp
authors.forename: Isao
authors.initials: I
authors.lastname: Momose
authors.forename: Yoji
authors.initials: Y
authors.lastname: Umezawa
authors.forename: Sehei
authors.initials: S
authors.lastname: Hirosawa
authors.forename: Masatomi
authors.initials: M
authors.lastname: Iijima
authors.forename: Hironobu
authors.initials: H
authors.lastname: Iinuma
authors.forename: Daishiro
authors.initials: D
authors.lastname: Ikeda
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002918:Chymotrypsin / Q000037:antagonists & inhibitors / Q000737:chemistry; D004151:Dipeptides / Q000737:chemistry* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry; D061988:Proteasome Inhibitors
chemical_list: C506903:1-naphthylacetyl-(O-methyl)-tyrosyl-valyl-(O-methyl)-tyrosinal; D000970:Antineoplastic Agents; D004151:Dipeptides; D009842:Oligopeptides; D061988:Proteasome Inhibitors; C449021:tyropeptin A; D002918:Chymotrypsin; D046988:Proteasome Endopeptidase Complex