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Ditopic Chelators of Dicopper Centers for Enhanced Tyrosinases Inhibition
- Source :
- Chemistry-A European Journal, Chemistry-A European Journal, 2021, 27 (13), pp.4384-4393. ⟨10.1002/chem.202004695⟩, Chemistry-A European Journal, Wiley-VCH Verlag, 2021, 27 (13), pp.4384-4393. ⟨10.1002/chem.202004695⟩
- Publication Year :
- 2020
-
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.
- 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
Subjects
Details
- ISSN :
- 15213765 and 09476539
- Volume :
- 27
- Issue :
- 13
- Database :
- OpenAIRE
- Journal :
- Chemistry (Weinheim an der Bergstrasse, Germany)
- Accession number :
- edsair.doi.dedup.....669b6b51157dfe553a3b23aa61824495