Inhibitors of tissue-nonspecific alkaline phosphatase: Design,synthesis, kinetics,biomineralization and cellular tests |
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Authors: | Julien Debray Lei Chang Stéphanie Marquès Stéphane Pellet-Rostaing Saida Mebarek René Buchet David Magne Florence Popowycz Marc Lemaire |
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Institution: | 1. Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, UMR-CNRS 5246, Equipe Catalyse Synthèse Environnement, Université de Lyon, Université Lyon 1, F-69622 Villeurbanne, France;2. Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, UMR-CNRS 5246, Equipe Organisation et Dynamique des Membranes Biologiques, Université de Lyon, Université Lyon 1, F-69622 Villeurbanne, France;3. Institut de Chimie Séparative de Marcoule, UMR-CNRS 5257, site de Marcoule, Université Montpellier 2, F-30207 Bagnols sur Cèze, France;4. Department of Biochemistry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland;5. Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, UMR-CNRS 5246, Equipe Chimie Organique et Bioorganique, INSA Lyon, F-69621 Villeurbanne, France |
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Abstract: | Chronic kidney disease (CKD) is associated with numerous metabolic and endocrine disturbances, including abnormalities of calcium and phosphate metabolism and an inflammatory syndrome. The latter occurs early in the course of CKD and contributes to the development and progression of vascular calcification. A few therapeutic strategies are today contemplated to target vascular calcification in patients with CKD: vitamin K2, calcimimetics and phosphate binders. However, none has provided complete prevention of vascular calcification and there is an urgent need for alternate efficient treatments. Recent findings indicate that tissue-nonspecific alkaline phosphatase (TNAP) may represent a very promising drug target due to its participation in mineralization by vascular smooth muscle cells. We report the synthesis of four levamisole derivatives having better inhibition property on TNAP than levamisole. Their IC50, Ki and water solubility have been determined. We found that the four inhibitors bind to TNAP in an uncompetitive manner and are selective to TNAP. Indeed, they do not inhibit intestinal and placental alkaline phosphatases. Survival MTT tests on human MG-63 and Saos-2 osteoblast-like cells have been performed in the presence of inhibitors. All the inhibitors are not toxic at concentrations that block TNAP activity. Moreover, they are able to significantly reduce mineralization in MG63 and Saos-2 osteoblast-like cells, indicating that they are promising molecules to prevent vascular calcification. |
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Keywords: | Alkaline phosphatase Enzyme Inhibitor Levamisole Vascular calcification |
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