Polyoxometalates—Potent and selective ecto-nucleotidase inhibitors

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 inhibit...

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Veröffentlicht in:Biochemical pharmacology 2015-01, Vol.93 (2), p.171-181
Hauptverfasser: Lee, Sang-Yong, Fiene, Amelie, Li, Wenjin, Hanck, Theodor, Brylev, Konstantin A., Fedorov, Vladimir E., Lecka, Joanna, Haider, Ali, Pietzsch, Hans-Jürgen, Zimmermann, Herbert, Sévigny, Jean, Kortz, Ulrich, Stephan, Holger, Müller, Christa E.
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container_end_page 181
container_issue 2
container_start_page 171
container_title Biochemical pharmacology
container_volume 93
creator Lee, Sang-Yong
Fiene, Amelie
Li, Wenjin
Hanck, Theodor
Brylev, Konstantin A.
Fedorov, Vladimir E.
Lecka, Joanna
Haider, Ali
Pietzsch, Hans-Jürgen
Zimmermann, Herbert
Sévigny, Jean
Kortz, Ulrich
Stephan, Holger
Müller, Christa E.
description 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: 3.88nM). Other investigated POMs selectively inhibited human NPP1, [TiW11CoO40]8− (4, PSB-POM141, Ki: 1.46nM) and [NaSb9W21O86]18− (6, PSB-POM143, Ki: 4.98nM) 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.
doi_str_mv 10.1016/j.bcp.2014.11.002
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Other investigated POMs selectively inhibited human NPP1, [TiW11CoO40]8− (4, PSB-POM141, Ki: 1.46nM) and [NaSb9W21O86]18− (6, PSB-POM143, Ki: 4.98nM) 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.</abstract><cop>England</cop><pub>Elsevier Inc</pub><pmid>25449596</pmid><doi>10.1016/j.bcp.2014.11.002</doi><tpages>11</tpages></addata></record>
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subjects Adenosine Triphosphatases - antagonists & inhibitors
Adenosine Triphosphatases - metabolism
Alkaline phosphatase
Animals
Cell Line, Tumor
Dose-Response Relationship, Drug
Ecto-5′-nucleotidase
Ecto-nucleotidase inhibitor
Enzyme Inhibitors - metabolism
Enzyme Inhibitors - pharmacology
Humans
Insecta
Mice
NPP1
NTPDase1
Phosphoric Diester Hydrolases - metabolism
Polyoxometalate
Sf9 Cells
Tungsten Compounds - metabolism
Tungsten Compounds - pharmacology
title Polyoxometalates—Potent and selective ecto-nucleotidase inhibitors
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