title: Polyoxometalates--potent and selective ecto-nucleotidase inhibitors.
abstract: Polyoxometalates (POMs) are inorganic cluster metal complexes that possess versatile biological activities, including antibacterial, anticancer, antidiabetic, and antiviral effects. Their mechanisms of action at the molecular level are largely unknown. However, it has been suggested that the inhibition of several enzyme families (e.g., phosphatases, protein kinases or ecto-nucleotidases) by POMs may contribute to their pharmacological properties. Ecto-nucleotidases are cell membrane-bound or secreted glycoproteins involved in the hydrolysis of extracellular nucleotides thereby regulating purinergic (and pyrimidinergic) signaling. They comprise four distinct families: ecto-nucleoside triphosphate diphosphohydrolases (NTPDases), ecto-nucleotide pyrophosphatases/phosphodiesterases (NPPs), alkaline phosphatases (APs) and ecto-5'-nucleotidase (eN). In the present study, we evaluated the inhibitory potency of a series of polyoxometalates as well as chalcogenide hexarhenium cluster complexes at a broad range of ecto-nucleotidases. [Co4(H2O)2(PW9O34)2](10-) (5, PSB-POM142) was discovered to be the most potent inhibitor of human NTPDase1 described so far (Ki: 3.88 nM). Other investigated POMs selectively inhibited human NPP1, [TiW11CoO40](8-) (4, PSB-POM141, Ki: 1.46 nM) and [NaSb9W21O86](18-) (6, PSB-POM143, Ki: 4.98 nM) representing the most potent and selective human NPP1 inhibitors described to date. [NaP5W30O110](14-) (8, PSB-POM144) strongly inhibited NTPDase1-3 and NPP1 and may therefore be used as a pan-inhibitor to block ATP hydrolysis. The polyoxoanionic compounds displayed a non-competitive mechanism of inhibition of NPPs and eN, but appeared to be competitive inhibitors of TNAP. Future in vivo studies with selected inhibitors identified in the current study are warranted.
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Sang-Yong
authors.initials: SY
authors.lastname: Lee
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Amelie
authors.initials: A
authors.lastname: Fiene
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Wenjin
authors.initials: W
authors.lastname: Li
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Theodor
authors.initials: T
authors.lastname: Hanck
authors.affiliation: Nikolaev Institute of Inorganic Chemistry, Siberian Branch of the Russia Academy of Sciences, 3 Acad. Lavrentiev prospect, 630090 Novosibirsk, Russia; Novosibirsk State University, 2 Pirogova Str., 630090 Novosibirsk, Russia.
authors.forename: Konstantin A
authors.initials: KA
authors.lastname: Brylev
authors.affiliation: Nikolaev Institute of Inorganic Chemistry, Siberian Branch of the Russia Academy of Sciences, 3 Acad. Lavrentiev prospect, 630090 Novosibirsk, Russia; Novosibirsk State University, 2 Pirogova Str., 630090 Novosibirsk, Russia.
authors.forename: Vladimir E
authors.initials: VE
authors.lastname: Fedorov
authors.affiliation: Département de Microbiologie-Infectiologie et d'Immunologie, Faculté de Médecine, Université Laval, Québec City, QC, Canada G1V 0A6; Centre de Recherche du CHU de Québec, Québec City, QC, Canada G1V 4G2.
authors.forename: Joanna
authors.initials: J
authors.lastname: Lecka
authors.affiliation: School of Engineering and Science, Campus Ring 8, Jacobs University, 28759 Bremen, Germany.
authors.forename: Ali
authors.initials: A
authors.lastname: Haider
authors.affiliation: Institute of Radiopharmaceutical Cancer Research, Helmholtz Zentrum Dresden-Rossendorf, Bautzner Landstrasse 400, 01328 Dresden, Germany.
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Pietzsch
authors.affiliation: Institute of Cell Biology and Neuroscience, Molecular and Cellular Neurobiology, Goethe University, 60438 Frankfurt am Main, Germany.
authors.forename: Herbert
authors.initials: H
authors.lastname: Zimmermann
authors.affiliation: Département de Microbiologie-Infectiologie et d'Immunologie, Faculté de Médecine, Université Laval, Québec City, QC, Canada G1V 0A6; Centre de Recherche du CHU de Québec, Québec City, QC, Canada G1V 4G2.
authors.forename: Jean
authors.initials: J
authors.lastname: Sévigny
authors.affiliation: School of Engineering and Science, Campus Ring 8, Jacobs University, 28759 Bremen, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kortz
authors.affiliation: Institute of Radiopharmaceutical Cancer Research, Helmholtz Zentrum Dresden-Rossendorf, Bautzner Landstrasse 400, 01328 Dresden, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Stephan
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany. Electronic address: christa.mueller@uni-bonn.de.
authors.forename: Christa E
authors.initials: CE
authors.lastname: Müller
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007313:Insecta; D051379:Mice; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D061987:Sf9 Cells; D017973:Tungsten Compounds / Q000378:metabolism* / Q000494:pharmacology*; D000099189:Lysophospholipase D; D000099294:Polyoxometalates
chemical_list: D000251:Adenosine Triphosphatases; D004791:Enzyme Inhibitors; D010727:Phosphoric Diester Hydrolases; D017973:Tungsten Compounds; D000099189:Lysophospholipase D; C102296:polyoxometalate I; D000099294:Polyoxometalates; C027201:ectoATPase
keywords: Alkaline phosphatase; Ecto-5′-nucleotidase; Ecto-nucleotidase inhibitor; NPP1; NTPDase1; Polyoxometalate