Synthesis of amino-hydroxy-benzocycloheptenones as potent, selective, non-peptidic dinuclear zinc metalloaminopeptidase inhibitors.
Racemic trisubstituted benzocycloheptanes were synthesized and evaluated for their ability to inhibit metalloaminopeptidase activities. A highly selective nanomolar inhibitor of a prototypical 'two zinc' aminopeptidase from the M28 family was observed with these tridentate species, while bidentate analogs proved to be highly selective for the 'one zinc' M1 family of enzymes. The selectivity profile of these new, low molecular weight structures may guide the design of specific, non-peptidic inhibitors of binuclear aminopeptidases.
Université de Haute Alsace, Laboratoire de Chimie Organique et Bioorganique, EA4466, ENSCMu, 3, rue Alfred Werner, F-68093 Mulhouse Cedex, France.
Mira
M
Al-Lakkis-Wehbe
Bérénice
B
Chaillou
Albert
A
Defoin
Sébastien
S
Albrecht
Céline
C
Tarnus
D000333:Aeromonas / Q000201:enzymology; D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001567:Benzocycloheptenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D020134:Catalytic Domain; D004926:Escherichia coli / Q000201:enzymology; D062105:Molecular Docking Simulation; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry
D001567:Benzocycloheptenes; D011480:Protease Inhibitors; D000626:Aminopeptidases; D015032:Zinc
M1 aminopeptidases; M28 aminopeptidases; Racemic trisubstituted benzocycloheptane derivatives; Selective inhibition; Synthetic inhibitors