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

• Published in: European journal of medicinal chemistry 2023-02, Vol.248, p.115090-115090, Article 115090
• Main Authors: Buitrago, Elina, Faure, Clarisse, Carotti, Marcello, Bergantino, Elisabetta, Hardré, Renaud, Maresca, Marc, Philouze, Christian, Vanthuyne, Nicolas, Boumendjel, Ahcène, Bubacco, Luigi, du Moulinet d’Hardemare, Amaury, Jamet, Hélène, Réglier, Marius, Belle, Catherine
• Format: Article
• Language: English
• Subjects: Amino Acids; Animals; Catalytic Domain; Chemical Sciences; Dicopper center; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Human tyrosinase; Humans; Inhibitor development; Mammals - metabolism; Melanin; Melanins; Melanoma, Experimental; Monophenol Monooxygenase
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.115090

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 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. [Display omitted] •Hydroxypyridine-N-oxide analogs prepared including a non-canonic amino acid.•Inhibition on tyrosinase enzymes from mushroom, bacterial and human sources tested.•Inhibition stereoselectivity demonstrated (enzymes and cell-based assays).