Exploiting HOPNO-dicopper center interaction to development of inhibitors for human tyrosinase - Université Grenoble Alpes Accéder directement au contenu
Article Dans Une Revue European Journal of Medicinal Chemistry Année : 2023

Exploiting HOPNO-dicopper center interaction to development of inhibitors for human tyrosinase

Résumé

In human, Tyrosinase enzyme (TyH) is involved in the key steps of protective pigments biosynthesis (in skin, eyes and hair). The use of molecules targeting its binuclear copper active site represents a relevant strategy to regulate TyH activities. In this work, we targeted 2-Hydroxypyridine-N-oxide analogs (HOPNO, an established chelating group for the tyrosinase dicopper active site) with the aim to combine effects induced by combination with a reference inhibitor (kojic acid) or natural substrate (tyrosine). The HOPNO-MeOH (3) and the racemic amino acid HOPNO-AA compounds (11) were tested on purified tyrosinases from different sources (fungal, bacterial and human) for comparison purposes. Both 2 compounds have more potent inhibitory activities than the parent HOPNO moiety and display strictly competitive inhibition constant, in particular with human tyrosinase. Furthermore, 11 appears to be the most active on the B16-F1 mammal melanoma cells. The investigations were completed by stereospecificity analysis. Racemic mixture of the fully protected amino acid 10 was separated by chiral HPLC into the corresponding enantiomers. Assignment of the absolute configuration of the deprotected compounds was completed, based on X-ray crystallography. The inhibition activities on melanin production were tested on lysates and whole human melanoma MNT-1 cells. Results showed significant enhancement of the inhibitory effects for the (S) enantiomer compared to the (R) enantiomer. Computational studies led to an explanation of this difference of activity based for both enantiomers on the respective position of the amino acid group versus the HOPNO plane.

Domaines

Chimie
Fichier principal
Vignette du fichier
EurJMedChemHAL.pdf (1002.26 Ko) Télécharger le fichier
Origine : Fichiers produits par l'(les) auteur(s)

Dates et versions

hal-03937610 , version 1 (13-01-2023)

Identifiants

Citer

Elina Buitrago, Clarisse Faure, Marcello Carotti, Elisabetta Bergantino, Renaud Hardré, et al.. Exploiting HOPNO-dicopper center interaction to development of inhibitors for human tyrosinase. European Journal of Medicinal Chemistry, 2023, 248, pp.115090. ⟨10.1016/j.ejmech.2023.115090⟩. ⟨hal-03937610⟩
61 Consultations
338 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More