Synthesis and biological evaluation of novel flavone-8-acetic acid derivatives as reversible inhibitors of aminopeptidase N/CD13.
The cell surface aminopeptidase N (APN/CD13), overexpressed in tumor cells, plays a critical role in angiogenesis. However, potent, selective, and, particularly, noncytotoxic inhibitors ot this protein are lacking, and the present work was undertaken with the aim of developing a new generation of noncytotoxic inhibitors that bind to APN/CD13. In this context, we have synthesized a series of novel flavone-8-acetic acid derivatives. Among the herein described and evaluated compounds, the 2',3-dinitroflavone-8-acetic acid (19b) proved to be the most efficient and exhibited an IC(50) of 25 microM which is 2.5 times higher than that of bestatin (1), the natural known inhibitor of APN/CD13. However, in contrast to bestatin (1), the dinitroflavone 19b did not induce any cytotoxicity to cultured human model cells. The presence of other substituents such as NO(2) or OCH(3) groups at the 3'- or 4'-position of the B phenyl group, or the existence of steric constraints (compounds 24 and 29), did not improve selectivity and potency. The flavone 19b affinity for APN/CD13 is not recovered with other proteases such as matrix metalloproteinase-9 (MMP-9), angiotensin converting enzyme (ACE/CD143), neutral endopeptidase (NEP/CD10), gamma-glutamyl transpeptidase (CD224), or the serine proteases dipeptidyl peptidase IV (DPPIV/CD26) or cathepsin G.
Bauvois
Brigitte
B
Unité 365 INSERM, Institut Curie, Section de Recherche, 26 rue d'Ulm, 75248 Paris Cedex 05, France.
Puiffe
Marie-Line
ML
Bongui
Jean-Bernard
JB
Paillat
Sandrine
S
Monneret
Claude
C
Dauzonne
Daniel
D
D000085:Acetates / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D018826:CD13 Antigens / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D005419:Flavonoids / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D005434:Flow Cytometry; D006801:Humans; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
C477198:3-nitro-2-(2-nitrophenyl)-4-oxo-4H-1-benzopyran-8-acetic acid; D000085:Acetates; D020533:Angiogenesis Inhibitors; D005419:Flavonoids; D011480:Protease Inhibitors; D018826:CD13 Antigens