title: Cyclopropenone-containing cysteine proteinase inhibitors. Synthesis and enzyme inhibitory activities.
abstract: By focusing on the amphiphilic properties of cyclopropenone (e.g. a good electrophile and a precursor for a stable 2pi-aromatic hydroxycyclopropenium cation), a new class of cysteine proteinase inhibitors containing a cyclopropenone moiety was designed. For the purpose of the present research, we needed to devise a new method to introduce a peptide-related moiety as a substituent on the cyclopropenone residue. We investigated the reaction of metalated cyclopropenone acetal derivatives (2, R2 = metal) with N-protected alpha-aminoaldehydes 4 to obtain the adduct 5, and succeeded in the preparation of highly potentiated cysteine proteinase inhibitors 8 after several steps transformations. They showed strong inhibitory activities only to cysteine proteinases such as calpain, papain, cathepsin B, and cathepsin L and not to serine (e.g. thrombin and cathepsin G) and aspartic proteinases (e.g. cathepsin D). Kinetic studies indicated that they are competitive inhibitors, and by the examinations of their inhibitory mechanism it became clear that they are reversible inhibitors.
authors.affiliation: Pharmaceuticals Laboratory 1, Yokohama Research Center, Mitsubishi Chemical Corporation, Japan. 1108189@cc.m-kagaku.co.jp
authors.forename: R
authors.initials: R
authors.lastname: Ando
authors.forename: T
authors.initials: T
authors.lastname: Sakaki
authors.forename: Y
authors.initials: Y
authors.lastname: Morinaka
authors.forename: C
authors.initials: C
authors.lastname: Takahashi
authors.forename: Y
authors.initials: Y
authors.lastname: Tamao
authors.forename: N
authors.initials: N
authors.lastname: Yoshii
authors.forename: S
authors.initials: S
authors.lastname: Katayama
authors.forename: K
authors.initials: K
authors.lastname: Saito
authors.forename: H
authors.initials: H
authors.lastname: Tokuyama
authors.forename: M
authors.initials: M
authors.lastname: Isaka
authors.forename: E
authors.initials: E
authors.lastname: Nakamura
mesh_terms: D002154:Calpain / Q000037:antagonists & inhibitors; D002401:Cathepsin B / Q000037:antagonists & inhibitors; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors; D003521:Cyclopropanes / Q000737:chemistry*; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics; D010450:Endopeptidases; D007700:Kinetics; D010206:Papain / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D003521:Cyclopropanes; D015853:Cysteine Proteinase Inhibitors; C120343:cyclopropenone; D002403:Cathepsins; D010450:Endopeptidases; D002154:Calpain; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; D056668:Cathepsin L; D010206:Papain