Preparation of novel specific aminopeptidase inhibitors with a cyclic imide skeleton

H. Takahashi, M. Komoda, Hiroki Kakuta, Y. Hashimoto

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

The studies on both structure-activity relationship study and identification of the target enzyme of novel nonpeptide aminopeptidase inhibitors with cyclic imide skeleton are reviewed. Some N-phenylphthalimide or N-phenylhomophthalimide derivative showed potent protease inhibitory activity in an assay system using human acute lymphoblastic leukemia cells, Molt-4, with alanin-4-methylcoumaryl-7-amide (ala-AMC) as a substrate. Especially, 2-(2,6-diethylphenyl)-1,2,3,4-tetrahydroisoquinoline-1,3-dione (PIQ-22) (3) was found to be the most potent inhibitor and further it showed potent tumor-cell invasion inhibitory activity that is more effective than potent peptide aminopeptidase inhibitors such as bestatin (1) or actinonin (2). For the further investigation of this novel protease inhibitory activity, we have carried out the structural development of PIQ-22 (3) and it is assumed that tautomerism of imidobenzoylketone in cyclic imide structure may be related to the inhibitory activity. The requirement for the activity of electron donating groups such as NH2 or OH to the condensed phenyl ring in phthalimide inhibitors also supports this possibility. The target aminopeptidase of PIQ-22 was identified as puromycin-sensitive aminopeptidase (PSA), by N-terminal amino acid sequencing, and by comparison with chromatographic behavior and substrate-selectivity, and so on. Lineweaver-Burk plot showed that PSA is inhibited by PIQ-22 (3) in a noncompetitive manner while puromycin (83) and bestatin (1) inhibit PSA competitively.

Original languageEnglish
Pages (from-to)909-921
Number of pages13
JournalYakugaku Zasshi
Volume120
Issue number10
Publication statusPublished - 2000
Externally publishedYes

Fingerprint

Imides
Aminopeptidases
Skeleton
Peptide Hydrolases
CD13 Antigens
Puromycin
Protein Sequence Analysis
Structure-Activity Relationship
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Electrons
Peptides
N-(2,6-diethylphenyl)homophthalimide
Enzymes
enkephalin degrading enzyme
Neoplasms
ubenimex

Keywords

  • N-phenylhomophthalimide
  • N-phenylphthalimide
  • Nonpeptide aminopeptidase inhibitor
  • Puromycin-sensitive aminopeptidase

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

Preparation of novel specific aminopeptidase inhibitors with a cyclic imide skeleton. / Takahashi, H.; Komoda, M.; Kakuta, Hiroki; Hashimoto, Y.

In: Yakugaku Zasshi, Vol. 120, No. 10, 2000, p. 909-921.

Research output: Contribution to journalArticle

Takahashi, H, Komoda, M, Kakuta, H & Hashimoto, Y 2000, 'Preparation of novel specific aminopeptidase inhibitors with a cyclic imide skeleton', Yakugaku Zasshi, vol. 120, no. 10, pp. 909-921.
Takahashi, H. ; Komoda, M. ; Kakuta, Hiroki ; Hashimoto, Y. / Preparation of novel specific aminopeptidase inhibitors with a cyclic imide skeleton. In: Yakugaku Zasshi. 2000 ; Vol. 120, No. 10. pp. 909-921.
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