[Preparation of novel specific aminopeptidase inhibitors with a cyclic imide skeleton].
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.
Takahashi
H
H
Institute of Molecular and Cellular Bioscience, University of Tokyo, Japan.
Komoda
M
M
Kakuta
H
H
Hashimoto
Y
Y
D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents; D006801:Humans; D007094:Imides; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology; D010797:Phthalimides; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D007094:Imides; D007546:Isoquinolines; C400282:N-(2,6-diethylphenyl)homophthalimide; D010797:Phthalimides; C037430:N-phenylphthalimide; D000626:Aminopeptidases