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

Elina Buitrago (1, 2) , Clarisse Faure (2) , Marcello Carotti (3) , Elisabetta Bergantino (3) , Renaud Hardré (4, 5) , Marc Maresca (5, 4) , Christian Philouze (1) , Nicolas Vanthuyne (4, 5) , Ahcène Boumendjel (1) , Luigi Bubacco (3) , Amaury Du Moulinet D’hardemare (1) , Hélène Jamet (1) , Marius Réglier (4, 5) , Catherine Belle (2)

1 DPM - Département de pharmacochimie moléculaire
2 DCM - Département de Chimie Moléculaire
3 Unipd - Università degli Studi di Padova = University of Padua
4 ISM2 - Institut des Sciences Moléculaires de Marseille
5 AMU - Aix Marseille Université

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.

Mots clés: Human Tyrosinase; Inhibitor development; Melanin; Dicopper center

Domaines: Chimie

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⟩