Novel cyclic-imide peptidomimetics as aminopeptidase N inhibitors. Structure-based design, chemistry and activity evaluation. II

• Published in: European journal of medicinal chemistry Vol. 45; no. 4; pp. 1618 - 1626
• Main Authors: Li, Qianbin, Fang, Hao, Wang, Xuejian, Xu, Wenfang
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 01.04.2010; Elsevier
• Subjects: Aminopeptidase N; Anti-tumor; Antineoplastic agents; Biological and medical sciences; CD13 Antigens - antagonists & inhibitors; Chemistry, Medicinal; Crystallography, X-Ray; Cyclic-imide; Drug Design; General aspects; HL-60 Cells; Humans; Imides - chemistry; K562 Cells; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Medical sciences; Models, Molecular; Molecular Mimicry; Peptides, Cyclic - chemistry; Peptides, Cyclic - pharmacology; Peptidomimetics; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Science & Technology; Spectrometry, Mass, Electrospray Ionization; Structure-Activity Relationship; Anti-tumor; Peptidomimetics; Aminopeptidase N; Cyclic-imide; CELLS; SITE; INVASION; ANGIOGENESIS; MECHANISM; ESCHERICHIA-COLI; DISCOVERY; Antineoplastic agent; Peptides; Nitrogen heterocycle; Leukemia; Tripeptide; Cytotoxicity; Modeling; Imide; Structure activity relation; Six membered ring; Molecular model; Chemical synthesis; Tumor cell; Ascitic hepatoma; Human; Enzyme; Aminopeptidases; Peptidomimetic compound; Rodentia; Hydroxamic acid; Enzyme inhibitor; Antimetastatic agent; Inhibitor enzyme complex; In vitro; HL60 cell line; Peptidases; In vivo; Vertebrata; Mammalia; Cell line; Mouse; Animal; Hydrolases; Membrane alanyl aminopeptidase
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2009.12.071

A novel class of potent aminopeptidase N inhibitors with 3-amino-cyclic-imide scaffold is described. The preliminary biological test revealed that all the compounds displayed high specific inhibitory activity against aminopeptidase N compared with previous work because of the existence of free amino group. Compounds containing hydroxamate group are more potent than carboxyl and ester derivatives. Compound 13f potentially inhibited APN activity with IC 50 value of 1.8 μM and displayed specific activity profiles in cells assay and in vivo anti-metastasis assay. [Display omitted]