Premium
Ditopic Chelators of Dicopper Centers for Enhanced Tyrosinases Inhibition
Author(s) -
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
Publication year - 2021
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202004695
Subject(s) - kojic acid , tyrosinase , chemistry , active site , moiety , enzyme , stereochemistry , semicarbazone , docking (animal) , biochemistry , melanin , binding site , chelation , combinatorial chemistry , organic chemistry , medicine , nursing
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.