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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. [ABSTRACT FROM AUTHOR]

Fluorescent ligands represent powerful tools for biological studies and are considered attractive alternatives to radioligands. In this study, we developed fluorescent antagonists for A 2B adenosine receptors (A 2B ARs), which are targeted by antiasthmatic xanthines and were proposed as novel targets in immuno-oncology. Our approach was to merge a small borondipyrromethene (BODIPY) derivative with the pharmacophore of 8-substituted xanthine derivatives. On the basis of the design, synthesis, and evaluation of model compounds, several fluorescent ligands were synthesized. Compound 29 (PSB-12105), which displayed high affinity for human, rat, and mouse A 2B ARs ( K i = 0.2-2 nM) and high selectivity for this AR subtype, was selected for further studies. A homology model of the human A 2B AR was generated, and docking studies were performed. Moreover, 29 allowed us to establish a homogeneous receptor-ligand binding assay using flow cytometry. These compounds constitute the first potent, selective fluorescent A 2B AR ligands and are anticipated to be useful for a variety of applications.