The soluble curcumin derivative NDS27 inhibits superoxide anion production by neutrophils and acts as substrate and reversible inhibitor of myeloperoxidase.

Autor: Franck T; Department of Clinical Sciences, Anesthesiology and Equine Surgery, Faculty of Veterinary Medicine, B 41, University of Liege, Sart Tilman, Liège, Belgium; Centre of Oxygen, Research and Development-CIRM, Institute of Chemistry B 6a, University of Liege, Sart Tilman, Liège, Belgium. Electronic address: t.franck@uliege.be., Aldib I; Laboratory of Pharmaceutical Chemistry & Analytical Platform of the Faculty of Pharmacy, Faculty of Pharmacy, Université Libre de Bruxelles, Brussels, Belgium., Zouaoui Boudjeltia K; Laboratory of Experimental Medicine, Université Libre de Bruxelles (ULB 222), CHU de Charleroi, Hôpital Vésale, Montigny-le-Tilleul, Belgium., Furtmüller PG; Department of Chemistry, Division of Biochemistry, BOKU, University of Natural Resources and Life Sciences, Vienna, Austria., Obinger C; Department of Chemistry, Division of Biochemistry, BOKU, University of Natural Resources and Life Sciences, Vienna, Austria., Neven P; Laboratory of Medicinal Chemistry-CIRM, Faculty of Pharmacy, B36, CHU Liège, Liège, Belgium., Prévost M; Structure and Function of Biological Membranes, Faculty of Sciences, Université Libre de Bruxelles, Brussels, Belgium., Soubhye J; Laboratory of Pharmaceutical Chemistry & Analytical Platform of the Faculty of Pharmacy, Faculty of Pharmacy, Université Libre de Bruxelles, Brussels, Belgium., Van Antwerpen P; Laboratory of Pharmaceutical Chemistry & Analytical Platform of the Faculty of Pharmacy, Faculty of Pharmacy, Université Libre de Bruxelles, Brussels, Belgium., Mouithys-Mickalad A; Centre of Oxygen, Research and Development-CIRM, Institute of Chemistry B 6a, University of Liege, Sart Tilman, Liège, Belgium., Serteyn D; Department of Clinical Sciences, Anesthesiology and Equine Surgery, Faculty of Veterinary Medicine, B 41, University of Liege, Sart Tilman, Liège, Belgium; Centre of Oxygen, Research and Development-CIRM, Institute of Chemistry B 6a, University of Liege, Sart Tilman, Liège, Belgium.
Jazyk: angličtina
Zdroj: Chemico-biological interactions [Chem Biol Interact] 2019 Jan 05; Vol. 297, pp. 34-43. Date of Electronic Publication: 2018 Oct 18.
DOI: 10.1016/j.cbi.2018.10.008
Abstrakt: A water-soluble curcumin lysinate incorporated into hydroxypropyl-β-cyclodextrin (NDS27) has been developed and shown anti-inflammatory properties but no comparative study has been made in parallel with its parent molecule, curcumin on polymorphonuclear neutrophils (PMNs) and myeloperoxidase (MPO) involved in inflammation. The effect of NDS27, its excipients (hydroxypropyl-β-cyclodextrin and lysine), curcumin lysinate and curcumin were compared on the release of superoxide anion by PMNs using a chemiluminescence assay and on the enzymatic activity of MPO. It was shown that curcumin and NDS27 exhibit similar inhibition activities on superoxide anion release by stimulated PMNs but also on MPO peroxidase and halogenation activities. The action mechanism of curcumin and NDS27 on the MPO activity was refined by stopped-flow and docking analyses. We demonstrate that both curcumin and NDS27 are reversible inhibitors of MPO by acting as excellent electron donors for redox intermediate Compound I (∼10 7  M -1  s -1 ) but not for Compound II (∼10 3  M -1  s -1 ) in the peroxidase cycle of the enzyme, thereby trapping the enzyme in the Compound II state. Docking calculations show that curcumin is able to enter the enzymatic pocket of MPO and bind to the heme cavity by π-stacking and formation of hydrogen bonds involving substituents from both aromatic rings. Hydroxypropyl-β-cyclodextrin is too bulky to enter MPO channel leading to the binding site suggesting a full release of curcumin from the cyclodextrin thereby allowing its full access to the active site of MPO. In conclusion, the hydroxypropyl-β-cyclodextrin of NDS27 enhances curcumin solubilization without affecting its antioxidant capacity and inhibitory activity on MPO.
(Copyright © 2018 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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