Specific nonpeptide inhibitors of puromycin-sensitive aminopeptidase with a 2,4(1H,3H)-quinazolinedione skeleton

Hiroki Kakuta, Aya Tanatani, Kazuo Nagasawa, Yuichi Hashimoto

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

Potent, specific, chemically stable and non-peptide/small-molecular inhibitors of puromycin-sensitive aminopeptidase, such as 3-(2,6-diethylphenyl)- 2,4(1H,3H)-quinazolinedione (PAQ-22, 5), were prepared by the structural development of a potent PSA inhibitor, 2-(2,6-diethylphenyl)-1,2,3,4- tetrahydroisoquinoline-1,3-dione (PIQ-22, 4). The design was carried out partly by applying electrostatic potential field information obtained from PIQ-22 (4) and its derivatives based on thalidomide (2). This information revealed that a positive electrostatic potential field around the benzylic methylene in the tetrahydroisoquinoline ring is necessary for potent activity. Lineweaver-Burk plot analysis showed that PAQ-22 (5) and its derivatives inhibit puromycin-sensitive aminopeptidase (PSA) in a non-competitive manner. These potent and specific PSA inhibitors showed dose-dependent cell invasion-inhibitory activity in a Matrigel assay using mouse melanoma B16F10/L5 cells, in spite of their low cell toxicity.

Original languageEnglish
Pages (from-to)1273-1282
Number of pages10
JournalChemical and Pharmaceutical Bulletin
Volume51
Issue number11
DOIs
Publication statusPublished - Nov 1 2003
Externally publishedYes

Keywords

  • Inhibitor
  • Puromycin-sensitive aminopeptidase
  • Quinazolinedione
  • Structure-activity relationship

ASJC Scopus subject areas

  • Chemistry(all)
  • Drug Discovery

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