The versatile binding mode of transition-state analogue inhibitors of tyrosinase towards dicopper(II) model complexes: experimental and theoretical investigations.
We describe 2-mercaptopyridine-N-oxide (HSPNO) as a new and efficient competitive inhibitor of mushroom tyrosinase (K(IC) =3.7 μM). Binding studies of HSPNO and 2-hydroxypyridine-N-oxide (HOPNO) on dinuclear copper(II) complexes [Cu(2)(BPMP)(μ-OH)](ClO(4))(2) (1; HBPMP=2,6-bis[bis(2-pyridylmethyl)aminomethyl]-4-methylphenol) and [Cu(2)(BPEP)(μ-OH)](ClO(4))(2)) (2; HBPEP=2,6-bis{bis[2-(2-pyridyl)ethyl]aminomethyl}-4-methylphenol), known to be functional models for the tyrosinase diphenolase activity, have been performed. A combination of structural data, spectroscopic studies, and DFT calculations evidenced the adaptable binding mode (bridging versus chelating) of HOPNO in relation to the geometry and chelate size of the dicopper center. For comparison, binding studies of HSPNO and kojic acid (5-hydroxy-2-(hydroxymethyl)-4-pyrone) on dinuclear complexes were performed. A theoretical approach has been developed and validated on HOPNO adducts to compare the binding mode on the model complexes. It has been applied for HSPNO and kojic acid. Although results for HSPNO were in line with those obtained with HOPNO, thus reflecting their chemical similarity, we showed that the bridging mode was the most preferential binding mode for kojic acid on both complexes.
Département de Chimie Moléculaire, Equipes CIRe et Chimie Théorique, Université J. Fourier, UMR 5250, ICMG FR-2607, BP 53, 38041 Grenoble, France.
Maylis
M
Orio
Constance
C
Bochot
Carole
C
Dubois
Gisèle
G
Gellon
Renaud
R
Hardré
Hélène
H
Jamet
Dominique
D
Luneau
Christian
C
Philouze
Marius
M
Réglier
Guy
G
Serratrice
Catherine
C
Belle
D001665:Binding Sites; D002614:Chelating Agents / Q000737:chemistry*; D003300:Copper / Q000737:chemistry*; D018360:Crystallography, X-Ray; D003497:Cyclic N-Oxides / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D008024:Ligands; D008958:Models, Molecular; D008962:Models, Theoretical; D008968:Molecular Conformation; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D009942:Organometallic Compounds / Q000737:chemistry* / Q000494:pharmacology*; D010636:Phenols / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry*; D013871:Thiones
C571063:2,6-bis(bis(2-pyridylmethyl)aminomethyl)-4-methylphenol; D002614:Chelating Agents; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D008024:Ligands; D009942:Organometallic Compounds; D010636:Phenols; D011725:Pyridines; D013871:Thiones; C008704:pyrithione; D003300:Copper; D014442:Monophenol Monooxygenase