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Jamshed Iqbal - One of the best experts on this subject based on the ideXlab platform.
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therapeutic potentials of ecto nucleoside triphosphate diphosphohydrolase ecto nucleotide pyrophosphatase phosphodiesterase ecto 5 Nucleotidase and alkaline phosphatase inhibitors
Medicinal Research Reviews, 2014Co-Authors: Mariya Alrashida, Jamshed IqbalAbstract:: The modulatory role of extracellular nucleotides and adenosine in relevance to purinergic cell signaling mechanisms has long been known and is an object of much research worldwide. These extracellular nucleotides are released by a variety of cell types either innately or as a response to patho-physiological stress or injury. A variety of surface-located ecto-Nucleotidases (of four major types; nucleoside triphosphate diphosphohydrolases or NTPDases, nucleotide pyrophosphatase/phosphodiesterases or NPPs, alkaline phosphatases APs or ALPs, and ecto-5'-Nucleotidase or e5NT) are responsible for meticulously controlling the availability of these important signaling molecules (at their respective receptors) in extracellular environment and are therefore crucial for maintaining the integrity of normal cell functioning. Overexpression of many of these ubiquitous ecto-enzymes has been implicated in a variety of disorders including cell adhesion, activation, proliferation, apoptosis, and degenerative neurological and immunological responses. Selective inhibition of these ecto-enzymes is an area that is currently being explored with great interest and hopes remain high that development of selective ecto-Nucleotidase inhibitors will prove to have many beneficial therapeutic implications. The aim of this review is to emphasize and focus on recent developments made in the field of inhibitors of ecto-Nucleotidases and to highlight their structure activity relationships wherever possible. Most recent and significant advances in field of NTPDase, NPP, AP, and e5NT inhibitors is being discussed in detail in anticipation of providing prolific leads and relevant background for research groups interested in synthesis of selective ecto-Nucleotidase inhibitors.
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Identification of sulfonic acids as efficient ecto-5'-Nucleotidase inhibitors.
European Journal of Medicinal Chemistry, 2013Co-Authors: Jamshed Iqbal, Rabia Raza, Norbert Furtmann, Joanna Lecka, Jean Sevigny, Abdul Hameed, Aamer Saeed, Abdul Matin, Jürgen BajorathAbstract:Abstract Ecto-5′-Nucleotidase (CD73) is well known for its implication in cancer. Inhibition of ecto-5′-Nucleotidases is thought to provide an attractive approach to cancer therapy. This study identifies sulfonic acid compounds as efficient inhibitors of ecto-5′-Nucleotidases. The compounds were tested against recombinant human and rat ecto-5′-Nucleotidases. The most potent new sulfonic acid inhibitor 6-amino-4-hydroxynaphthalene-2-sulfonic acid (1) of ecto-5′-Nucleotidase had an IC50 of 1.32 ± 0.09 μM for the human and 10.4 ± 3.3 μM for the rat enzyme. Generally, all compounds were more active against the human enzyme. Plausible binding mode models were developed for this new class of inhibitors. Furthermore, several sulfonic acid inhibitors were efficient cytotoxic agents when tested on H157 cancer cell lines. Hence, new ecto-5′-Nucleotidases inhibitors displayed significant potential for further development as compounds for anti-cancer therapy.
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Identification of Small Molecule Sulfonic Acids as Ecto-5'-Nucleotidase Inhibitors
Medicinal chemistry (Shariqah (United Arab Emirates)), 2012Co-Authors: Rabia Raza, Joanna Lecka, Jean Sevigny, Aamer Saeed, Jamshed IqbalAbstract:Ecto-5'-Nucleotidase inhibitors have great potential as anti-tumor agents. We have investigated biochemical properties of human and rat ecto-5'-Nucleotidases and characterized 19 small molecule sulfonic acid derivatives as potential inhibitors of ecto-5'-Nucleotidases. We identified 11 potent inhibitors of human and rat ecto-5'-Nucleotidases and checked their selectivity. Compound 10 (Sodium 2,4-dinitrobenzenesulfonate) with Ki value of 0.66 M and 19 (N-(4- sulfamoylphenylcarbamothioyl) pivalamide) with Ki value of 0.78 M were identified as the most potent inhibitors for human and rat ecto-5'-Nucleotidase, respectively. The present compounds have low molecular weights, water solubility and equal potency as compared to the reported inhibitors.
Jean Sevigny - One of the best experts on this subject based on the ideXlab platform.
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Characterization of ecto-Nucleotidases in human oviducts with an improved approach simultaneously identifying protein expression and in situ enzyme activity
Histochemistry and Cell Biology, 2018Co-Authors: María Lina Villamonte, Jean Sevigny, Benjamín Torrejón-escribano, Aitor Rodríguez-martínez, Carla Trapero, August Vidal, Inmaculada Gómez De Aranda, Xavier Matías-guiu, Mireia Martín-satuéAbstract:Extracellular ATP and its hydrolysis product adenosine modulate various reproductive functions such as those taking place in oviducts, including contraction, beating of cilia, and maintenance of fluid composition that, in turn, influences sperm capacitation and hyperactivation, as well as oocyte and embryo nourishing. Ecto-Nucleotidases are the enzymes that regulate extracellular ATP and adenosine levels, thus playing a role in reproduction. We have optimized a convenient method for characterizing ecto-Nucleotidases that simultaneously localizes the protein and its associated enzyme activity in the same tissue slice and characterizes ecto-Nucleotidases in human oviducts. The technique combines immunofluorescence and in situ histochemistry, allowing precise identification of ecto-Nucleotidases at a subcellular level. In oviducts, remarkably, ectonucleoside triphosphate diphosphohydrolase 2 (NTPDase2) and NTPDase3, with the ability to hydrolyze ATP to AMP, are expressed in ciliated epithelial cells but with different subcellular localization. Ecto-5′Nucleotidase/CD73 is also expressed apically in ciliated cells. CD73, together with alkaline phosphatase, also expressed apically in oviductal epithelium, complete the hydrolysis sequence by dephosphorylating AMP to adenosine. The concerted action of these enzymes would contribute to the local increase of adenosine concentration necessary for sperm capacitation. The use of this method would be an asset for testing new potential therapeutic drugs with inhibitory potential, which is of great interest presently in the field of oncology and in other clinical disciplines.
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Rat submandibular glands secrete nanovesicles with NTPDase and 5′-Nucleotidase activities
Purinergic Signalling, 2015Co-Authors: Débora A. González, Claude Hattab, Jean Sevigny, Patricia Egido, Noelia B. Balcarcel, Martín M. Barbieri Van Haaster, Julie Pelletier, Mariano A. OstuniAbstract:Extracellular nucleotides modulate a wide number of biological processes such as neurotransmission, platelet aggregation, muscle contraction, and epithelial secretion acting by the purinergic pathway. Nucleotidases as NTPDases and ecto-5′-Nucleotidase are membrane-anchored proteins that regulate extracellular nucleotide concentrations. In a previous work, we have partially characterized an NTPDase-like activity expressed by rat submandibular gland microsomes, giving rise to the hypothesis that membrane NTPDases could be released into salivary ducts to regulate luminal nucleotide concentrations as was previously proposed for ovarian, prostatic, and pancreatic secretions. Present results show that rat submandibular glands incubated in vitro release membrane-associated NTPDase and ecto-5′-Nucleotidase activities. Electron microscopy images show that released membranes presenting Nucleotidase activity correspond to exosome-like vesicles which are also present at microsomal fraction. Both exosome release and Nucleotidase activities are raised by adrenergic stimulation. Nucleotidase activities present the same kinetic characteristics than microsomal Nucleotidase activity, corresponding mainly to the action of NTPDase2 and NTPDase3 isoforms as well as 5′-Nucleotidase. This is consistent with Western blot analysis revealing the presence of these enzymes in the microsomal fraction.
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Identification of sulfonic acids as efficient ecto-5'-Nucleotidase inhibitors.
European Journal of Medicinal Chemistry, 2013Co-Authors: Jamshed Iqbal, Rabia Raza, Norbert Furtmann, Joanna Lecka, Jean Sevigny, Abdul Hameed, Aamer Saeed, Abdul Matin, Jürgen BajorathAbstract:Abstract Ecto-5′-Nucleotidase (CD73) is well known for its implication in cancer. Inhibition of ecto-5′-Nucleotidases is thought to provide an attractive approach to cancer therapy. This study identifies sulfonic acid compounds as efficient inhibitors of ecto-5′-Nucleotidases. The compounds were tested against recombinant human and rat ecto-5′-Nucleotidases. The most potent new sulfonic acid inhibitor 6-amino-4-hydroxynaphthalene-2-sulfonic acid (1) of ecto-5′-Nucleotidase had an IC50 of 1.32 ± 0.09 μM for the human and 10.4 ± 3.3 μM for the rat enzyme. Generally, all compounds were more active against the human enzyme. Plausible binding mode models were developed for this new class of inhibitors. Furthermore, several sulfonic acid inhibitors were efficient cytotoxic agents when tested on H157 cancer cell lines. Hence, new ecto-5′-Nucleotidases inhibitors displayed significant potential for further development as compounds for anti-cancer therapy.
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Identification of Small Molecule Sulfonic Acids as Ecto-5'-Nucleotidase Inhibitors
Medicinal chemistry (Shariqah (United Arab Emirates)), 2012Co-Authors: Rabia Raza, Joanna Lecka, Jean Sevigny, Aamer Saeed, Jamshed IqbalAbstract:Ecto-5'-Nucleotidase inhibitors have great potential as anti-tumor agents. We have investigated biochemical properties of human and rat ecto-5'-Nucleotidases and characterized 19 small molecule sulfonic acid derivatives as potential inhibitors of ecto-5'-Nucleotidases. We identified 11 potent inhibitors of human and rat ecto-5'-Nucleotidases and checked their selectivity. Compound 10 (Sodium 2,4-dinitrobenzenesulfonate) with Ki value of 0.66 M and 19 (N-(4- sulfamoylphenylcarbamothioyl) pivalamide) with Ki value of 0.78 M were identified as the most potent inhibitors for human and rat ecto-5'-Nucleotidase, respectively. The present compounds have low molecular weights, water solubility and equal potency as compared to the reported inhibitors.
Jürgen Bajorath - One of the best experts on this subject based on the ideXlab platform.
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Identification of sulfonic acids as efficient ecto-5'-Nucleotidase inhibitors.
European Journal of Medicinal Chemistry, 2013Co-Authors: Jamshed Iqbal, Rabia Raza, Norbert Furtmann, Joanna Lecka, Jean Sevigny, Abdul Hameed, Aamer Saeed, Abdul Matin, Jürgen BajorathAbstract:Abstract Ecto-5′-Nucleotidase (CD73) is well known for its implication in cancer. Inhibition of ecto-5′-Nucleotidases is thought to provide an attractive approach to cancer therapy. This study identifies sulfonic acid compounds as efficient inhibitors of ecto-5′-Nucleotidases. The compounds were tested against recombinant human and rat ecto-5′-Nucleotidases. The most potent new sulfonic acid inhibitor 6-amino-4-hydroxynaphthalene-2-sulfonic acid (1) of ecto-5′-Nucleotidase had an IC50 of 1.32 ± 0.09 μM for the human and 10.4 ± 3.3 μM for the rat enzyme. Generally, all compounds were more active against the human enzyme. Plausible binding mode models were developed for this new class of inhibitors. Furthermore, several sulfonic acid inhibitors were efficient cytotoxic agents when tested on H157 cancer cell lines. Hence, new ecto-5′-Nucleotidases inhibitors displayed significant potential for further development as compounds for anti-cancer therapy.
Linda F. Thompson - One of the best experts on this subject based on the ideXlab platform.
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Physiological roles for ecto-5’-Nucleotidase (CD73)
Purinergic Signalling, 2006Co-Authors: Sean P. Colgan, Holger K. Eltzschig, Tobias Eckle, Linda F. ThompsonAbstract:Nucleotides and nucleosides influence nearly every aspect of physiology and pathophysiology. Extracellular nucleotides are metabolized through regulated phosphohydrolysis by a series of ecto-Nucleotidases. The formation of extracellular adenosine from adenosine 5’-monophosphate is accomplished primarily through ecto-5’-Nucleotidase (CD73), a glycosyl phosphatidylinositol-linked membrane protein found on the surface of a variety of cell types. Recent in vivo studies implicating CD73 in a number of tissue protective mechanisms have provided new insight into its regulation and function and have generated considerable interest. Here, we review contributions of CD73 to cell and tissue stress responses, with a particular emphasis on physiologic responses to regulated CD73 expression and function, as well as new findings utilizing Cd73 -deficient animals.
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physiological roles for ecto 5 Nucleotidase cd73
Purinergic Signalling, 2006Co-Authors: Sean P. Colgan, Linda F. Thompson, Holger K. Eltzschig, Tobias EckleAbstract:Nucleotides and nucleosides influence nearly every aspect of physiology and pathophysiology. Extracellular nucleotides are metabolized through regulated phosphohydrolysis by a series of ecto-Nucleotidases. The formation of extracellular adenosine from adenosine 5’-monophosphate is accomplished primarily through ecto-5’-Nucleotidase (CD73), a glycosyl phosphatidylinositol-linked membrane protein found on the surface of a variety of cell types. Recent in vivo studies implicating CD73 in a number of tissue protective mechanisms have provided new insight into its regulation and function and have generated considerable interest. Here, we review contributions of CD73 to cell and tissue stress responses, with a particular emphasis on physiologic responses to regulated CD73 expression and function, as well as new findings utilizing Cd73-deficient animals.
Joanna Lecka - One of the best experts on this subject based on the ideXlab platform.
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polyoxometalates potent and selective ecto Nucleotidase inhibitors
Biochemical Pharmacology, 2015Co-Authors: Sangyong Lee, Joanna Lecka, Amelie Fiene, Theodor Hanck, Konstantin A Brylev, V E Fedorov, Ali Haider, Hansjurgen PietzschAbstract: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. [Co 4 (H 2 O) 2 (PW 9 O 34 ) 2 ] 10− ( 5 , PSB-POM142) was discovered to be the most potent inhibitor of human NTPDase1 described so far ( K i : 3.88 nM). Other investigated POMs selectively inhibited human NPP1, [TiW 11 CoO 40 ] 8− ( 4 , PSB-POM141, K i : 1.46 nM) and [NaSb 9 W 21 O 86 ] 18− ( 6 , PSB-POM143, K i : 4.98 nM) representing the most potent and selective human NPP1 inhibitors described to date. [NaP 5 W 30 O 110 ] 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.
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Identification of sulfonic acids as efficient ecto-5'-Nucleotidase inhibitors.
European Journal of Medicinal Chemistry, 2013Co-Authors: Jamshed Iqbal, Rabia Raza, Norbert Furtmann, Joanna Lecka, Jean Sevigny, Abdul Hameed, Aamer Saeed, Abdul Matin, Jürgen BajorathAbstract:Abstract Ecto-5′-Nucleotidase (CD73) is well known for its implication in cancer. Inhibition of ecto-5′-Nucleotidases is thought to provide an attractive approach to cancer therapy. This study identifies sulfonic acid compounds as efficient inhibitors of ecto-5′-Nucleotidases. The compounds were tested against recombinant human and rat ecto-5′-Nucleotidases. The most potent new sulfonic acid inhibitor 6-amino-4-hydroxynaphthalene-2-sulfonic acid (1) of ecto-5′-Nucleotidase had an IC50 of 1.32 ± 0.09 μM for the human and 10.4 ± 3.3 μM for the rat enzyme. Generally, all compounds were more active against the human enzyme. Plausible binding mode models were developed for this new class of inhibitors. Furthermore, several sulfonic acid inhibitors were efficient cytotoxic agents when tested on H157 cancer cell lines. Hence, new ecto-5′-Nucleotidases inhibitors displayed significant potential for further development as compounds for anti-cancer therapy.
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Identification of Small Molecule Sulfonic Acids as Ecto-5'-Nucleotidase Inhibitors
Medicinal chemistry (Shariqah (United Arab Emirates)), 2012Co-Authors: Rabia Raza, Joanna Lecka, Jean Sevigny, Aamer Saeed, Jamshed IqbalAbstract:Ecto-5'-Nucleotidase inhibitors have great potential as anti-tumor agents. We have investigated biochemical properties of human and rat ecto-5'-Nucleotidases and characterized 19 small molecule sulfonic acid derivatives as potential inhibitors of ecto-5'-Nucleotidases. We identified 11 potent inhibitors of human and rat ecto-5'-Nucleotidases and checked their selectivity. Compound 10 (Sodium 2,4-dinitrobenzenesulfonate) with Ki value of 0.66 M and 19 (N-(4- sulfamoylphenylcarbamothioyl) pivalamide) with Ki value of 0.78 M were identified as the most potent inhibitors for human and rat ecto-5'-Nucleotidase, respectively. The present compounds have low molecular weights, water solubility and equal potency as compared to the reported inhibitors.
