Ditopic Chelators of Dicopper Centers for Enhanced Tyrosinases Inhibition

• Published in: Chemistry : a European journal 2021-03, Vol.27 (13), p.4384-4393
• Main Authors: Buitrago, Elina, Faure, Clarisse, Challali, Lylia, Bergantino, Elisabetta, Boumendjel, Ahcène, Bubacco, Luigi, Carotti, Marcello, Hardré, Renaud, Maresca, Marc, Philouze, Christian, Jamet, Hélène, Réglier, Marius, Belle, Catherine
• Format: Article
• Language: English
• Subjects: Agaricales - metabolism; Binding; bioinorganic chemistry; Biosynthesis; Chelating Agents; Chelation; Chemical Sciences; Chemistry; Computer applications; Coordination chemistry; copper active sites; ditopic inhibitors; docking; Enzymatic activity; Enzyme Inhibitors - pharmacology; Enzymes; Humans; Kojic acid; Lysates; Medicinal Chemistry; Melanin; Melanoma; Monophenol Monooxygenase - metabolism; Mushrooms; Pigments; Structure-Activity Relationship; Tyrosinase; tyrosinases
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.202004695

Tyrosinase enzymes (Tys) are involved in the key steps of melanin (protective pigments) biosynthesis and molecules targeting the binuclear copper active site on tyrosinases represent a relevant strategy to regulate enzyme activities. In this work, the possible synergic effect generated by a combination of known inhibitors is studied. For this, derivatives containing kojic acid (KA) and 2‐hydroxypyridine‐N‐oxide (HOPNO) combined with a thiosemicarbazone (TSC) moiety were synthetized. Their inhibition activities were evaluated on purified tyrosinases from different sources (mushroom, bacterial, and human) as well as on melanin production by lysates from the human melanoma MNT‐1 cell line. Results showed significant enhancement of the inhibitory effects compared with the parent compounds, in particular for HOPNO‐TSC. To elucidate the interaction mode with the dicopper(II) active site, binding studies with a tyrosinase bio‐inspired model of the dicopper(II) center were investigated. The structure of the isolated adduct between one ditopic inhibitor (KA‐TSC) and the model complex reveals that the binding to a dicopper center can occur with both chelating sites. Computational studies on model complexes and docking studies on enzymes led to the identification of KA and HOPNO moieties as interacting groups with the dicopper active site. Ty combined: The combination of known tyrosinase (Ty) inhibitors improves inhibition activities, which is tested and compared for isolated enzymes (fungal, bacterial, and human). The interaction mode with the dicopper active site is discussed by using a functional model of the active site associated with theoretical modeling. One ditopic compound displays melanogenesis suppression in melanoma cells.