Cyclopropenone-containing cysteine proteinase inhibitors. Synthesis and enzyme inhibitory activities

Ryoichi Ando, Toshiro Sakaki, Yasuhiro Morinaka, Chizuko Takahashi, Yoshikuni Tamao, Narihiko Yoshii, Sota Katayama, Ken Ichi Saito, Hidetoshi Tokuyama, Masahiko Isaka, Eiichi Nakamura

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)

Abstract

By focusing on the amphiphilic properties of cyclopropenone (e.g. a good electrophile and a precursor for a stable 2π-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 α-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 asparatic protainases (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. Copyright (C) 1999 Elsevier Science Ltd.

Original languageEnglish
Pages (from-to)571-579
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume7
Issue number4
DOIs
Publication statusPublished - 1999 Apr 1
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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