Binding of 2-Hydroxypyridine-N-oxide on Dicopper(II) Centers: Insights into Tyrosinase Inhibition Mechanism by Transition-State Analogs

• Published in: Inorganic chemistry 2009-12, Vol.48 (23), p.10874-10876
• Main Authors: Peyroux, Eugénie, Ghattas, Wadih, Hardré, Renaud, Giorgi, Michel, Faure, Bruno, Simaan, A. Jalila, Belle, Catherine, Réglier, Marius
• Format: Article
• Language: English
• Subjects: Binding Sites; Chemical Sciences; Copper - chemistry; Crystallography, X-Ray; Cyclic N-Oxides - chemistry; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Models, Molecular; Molecular Conformation; Monophenol Monooxygenase - antagonists & inhibitors; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; Pyridines - chemistry; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0020-1669; 1520-510X
• DOI: 10.1021/ic901593x

2-Hydroxypyridine-N-oxide (HOPNO) is described as a new and efficient transition-state analog (TS-analog) inhibitor for the mushroom tyrosinase with an IC50 = 1.16 μM and a KI = 1.8 μM. Using the binuclear copper(II) complex [Cu2(BPMP)(μ−OH)](ClO4)2 (2) known as a functional model for the tyrosinase catecholase activity, we isolated and fully characterized a 1:1 (2)/OPNO adduct in which the HOPNO is deprotonated and chelates only one Cu-atom of the binuclear site in a bidentate mode. On the basis of these results, a structural model for the tyrosinase inhibition by HOPNO is proposed.