1. Ditopic Chelators of Dicopper Centers for Enhanced Tyrosinases Inhibition
- Author
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Christian Philouze, Elina Buitrago, Lylia Challali, Marc Maresca, Elisabetta Bergantino, Ahcène Boumendjel, Marius Réglier, Marcello Carotti, Luigi Bubacco, Catherine Belle, Clarisse Faure, Hélène Jamet, Renaud Hardré, Département de Chimie Moléculaire (DCM), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Università degli Studi di Padova = University of Padua (Unipd), Département de pharmacochimie moléculaire (DPM), Institut des Sciences Moléculaires de Marseille (ISM2), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), ANR-11-LABX-0003,ARCANE,Grenoble, une chimie bio-motivée(2011), ANR-15-IDEX-0002,UGA,IDEX UGA(2015), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), Université Grenoble Alpes (UGA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Universita degli Studi di Padova
- Subjects
bioinorganic chemistry ,copper active sites ,ditopic inhibitors ,docking ,tyrosinases ,Chelating Agents ,Enzyme Inhibitors ,Humans ,Structure-Activity Relationship ,Agaricales ,Monophenol Monooxygenase ,Stereochemistry ,Tyrosinase ,[CHIM.THER]Chemical Sciences/Medicinal Chemistry ,010402 general chemistry ,01 natural sciences ,Catalysis ,Melanin ,chemistry.chemical_compound ,Moiety ,Chelation ,[CHIM.COOR]Chemical Sciences/Coordination chemistry ,chemistry.chemical_classification ,biology ,010405 organic chemistry ,Organic Chemistry ,Active site ,General Chemistry ,0104 chemical sciences ,Enzyme ,chemistry ,Docking (molecular) ,biology.protein ,Kojic acid - Abstract
International audience; 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, we studied the possible synergic effect generated by combination of known inhibitors. 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 human melanoma MNT-1 cell line. Results showed significant enhancement of the inhibitory effects compared to the parent compounds, in particular for HOPNO-TSC. In order to elucidate the interaction mode with the dicopper(II) active site, we investigated the binding studies towards a tyrosinase bio-inspired model of the dicopper(II) center. 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.
- Published
- 2020