Synthesis of {[5-(adenin-9-yl)-2-furyl]methoxy}methyl phosphonic acid and evaluations against human adenylate kinases |
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| Affiliation: | 1. Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-UM 1-UM 2, cc 1705, Université Montpellier 2, Place Eugène Bataillon, 34095 Montpellier cedex 5, France;2. Enzymologie Moléculaire et Fonctionnelle, UMR 8256 UPMC-CNRS, ERL INSERM U1164, Université Pierre et Marie Curie, 7 Quai St-Bernard, 75252 Paris cedex 5, France;1. Department of Actinobacteria Metabolic Engineering Group, Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Campus C2 3, 66123 Saarbrücken, Germany;2. Institute for Organic Chemistry II, University Siegen, Adolf-Reichwein-Str. 2, 57076 Siegen, Germany;3. Institute for Pharmaceutical Biology and Biotechnology, Albert-Ludwigs University Freiburg, Stefan-Meier-Str. 19, 79104 Freiburg, Germany;1. P.N. Lebedev Physical Institute of RAS, Samara Branch, Samara 443011, Russia;2. Department of Chemistry, Emory University, Atlanta, GA 30322, USA;1. Max Planck Institute for Mathematics, Bonn, Germany;2. Instituto de Matemática y Física, Universidad de Talca, Casilla 721, Talca, Chile;1. Department of Mathematics, Stanford University, United States;2. Department of Mathematics, University of Toledo, United States |
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| Abstract: | AMP mimics constitute an important class of therapeutic derivatives to treat diseases where the pool of ATP is involved. A new phosphonate derivative of 9-(5-hydroxymethylfuran-2-yl)adenine was synthesized in a multi-step sequence from commercially available adenosine. Its ability to behave as a substrate of human adenylate kinases 1 and 2 was assessed. The phosphonate was shown to be a moderate but selective substrate of the mitochondrial human AK2, better than well-known antiviral acyclic phosphonates 9-(2-phosphonomethoxyethyl)adenine (PMEA, Adefovir) and (R)-9-(2-phosphonomethoxypropyl)adenine (PMPA, Tenofovir). Putative binding mode within adenylate kinase NMP site revealed by molecular docking in comparison to AMP native substrate allowed to illustrate this selective behavior. |
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| Keywords: | Adenosine Analogue/AMP mimics Phosphotransfer Nucleoside Phosphonate Kinase |
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