18837-50-8Relevant articles and documents
Inhibitors for the bacterial ectonucleotidase Lp1NTPDase from Legionella pneumophila
Fiene, Amelie,Baqi, Younis,Malik, Enas M.,Newton, Patrice,Li, Wenjin,Lee, Sang-Yong,Hartland, Elizabeth L.,Müller, Christa E.
, p. 4363 - 4371 (2016)
Legionella pneumophila is an aerobic, Gram-negative bacterium of the genus Legionella, which constitutes the major causative agent of Legionnaires’ disease. Recently a nucleoside triphosphate diphosphohydrolase (NTPDase) from L. pneumophila was identified and termed Lp1NTPDase; it was found to be a structural and functional homolog of mammalian NTPDases catalyzing the hydrolysis of ATP to ADP and ADP to AMP. Its activity is believed to contribute to the virulence of Legionella pneumophila. Therefore Lp1NTPDase inhibitors are considered as novel antibacterial drugs. However, only weakly potent compounds are available so far. In the present study, a capillary electrophoresis (CE)-based enzyme assay for monitoring the Lp1NTPDase activity was established. The enzymatic reaction was performed in a test tube followed by separation of substrate and products by CE and subsequent quantification by UV analysis. After kinetic characterization of the enzyme, a series of 1-amino-4-ar(alk)ylamino-2-sulfoanthraquinone derivatives structurally related to the anthraquinone dye Reactive Blue 2, a non-selective ecto-NTPDase inhibitor, was investigated for inhibitory activity on Lp1NTPDase using the CE-based enzyme assay. Derivatives bearing a large lipophilic substituent (e.g., fused aromatic rings) in the 4-position of the 1-amino-2-sulfoanthraquinone showed the highest inhibitory activity. Compounds with IC50values in the low micromolar range were identified. The most potent inhibitor was 1-amino-4-[phenanthrene-9-yl-amino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (28, PSB-16131), with an IC50-value of 4.24?μM. It represents the most potent Lp1NTPDase inhibitor described to date. These findings may serve as a starting point for further optimization. Lp1NTPDase inhibition provides a novel approach for the (immuno)therapy of Legionella infections.
Development of Potent and Selective Antagonists for the UTP-Activated P2Y4 Receptor
Rafehi, Muhammad,Malik, Enas M.,Neumann, Alexander,Abdelrahman, Aliaa,Hanck, Theodor,Namasivayam, Vigneshwaran,Müller, Christa E.,Baqi, Younis
, p. 3020 - 3038 (2017/04/21)
P2Y4 is a Gq protein-coupled receptor activated by uridine-5′-triphosphate (UTP), which is widely expressed in the body, e.g., in intestine, heart, and brain. No selective P2Y4 receptor antagonist has been described so far. Therefore, we developed and optimized P2Y4 receptor antagonists based on an anthraquinone scaffold. Potency was assessed by a fluorescence-based assay measuring inhibition of UTP-induced intracellular calcium release in 1321N1 astrocytoma cells stably transfected with the human P2Y4 receptor. The most potent compound of the present series, sodium 1-amino-4-[4-(2,4-dimethylphenylthio)phenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (PSB-16133, 61) exhibited an IC50 value of 233 nM, selectivity versus other P2Y receptor subtypes, and is thought to act as an allosteric antagonist. A receptor homology model was built and docking studies were performed to analyze ligand-receptor interactions. Compound 64 (PSB-1699, sodium 1-amino-4-[4-(3-pyridin-3-ylmethylthio)phenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate) represents the most selective P2Y4 receptor antagonist known to date. Compounds 61 and 64 are therefore anticipated to become useful tools for studying this scarcely investigated receptor.
High-affinity, non-nucleotide-derived competitive antagonists of platelet P2Y12 receptors
Baqi, Younis,Atzler, Kerstin,K?se, Meryem,Gl?nzel, Markus,Müller, Christa E.
supporting information; experimental part, p. 3784 - 3793 (2010/04/24)
Anthraquinone derivatives related to the moderately potent, nonselective P2Y12 receptor antagonist reactive blue 2 (6) have been synthesized and optimized with respect to P2Y12 receptor affinity. A radioligand binding assay utilizing human blood platelet membranes and the P2Y12 receptor-selective antagonist radioligand [3H]2-propylthioadenosine- 5′-adenylic acid (1,1-dichloro-1-phosphonomethyl-1-phosphonyl) anhydride ([3H]PSB-0413) was applied for compound testing. 1-Amino-2- sulfoanthraquinone derivatives bearing a (p-phenylamino) anilino substitution in the 4-position and an additional acidic function in the meta-position of the aniline ring showed high P2Y12 receptor affinity. These new anthraquinone derivatives became accessible by a recently developed copper(0)-catalyzed Ullmann coupling reaction of 1-amino-4-bromoanthraquinone derivatives with anilines in phosphate buffer under microwave irradiation. The most potent compounds exhibited Ki values of 24.9 nM (1-amino-4-[4-phenylamino-3-sulfophenylamino]-9,10-dioxo-9,10-dihydroanthracene- 2-sulfonate, PSB-0739, 39), and 21.0 nM (1-amino-4-[4-phenylamino-3- carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, PSB-0702, 41), respectively. 1-Amino-2-sulfo-4-anilinoanthraquinone derivatives appeared to be noncytotoxic, as shown for selected derivatives at two human cell lines (melanoma and astrocytoma). Compounds 39 and 41 represent new lead structures for the development of antithrombotic drugs.
