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Structure-activity relationships of anthraquinone derivatives derived from bromaminic acid as inhibitors of ectonucleoside triphosphate diphosphohydrolases (E-NTPDases)

By Younis Baqi, Stefanie Weyler, Jamshed Iqbal, Herbert Zimmermann and Christa E. Müller

Abstract

Reactive blue 2 (RB-2) had been characterized as a relatively potent ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) inhibitor with some selectivity for NTPDase3. In search for the pharmacophore and to analyze structure-activity relationships we synthesized a series of truncated derivatives and analogs of RB-2, including 1-amino-2-sulfo-4-ar(alk)ylaminoanthraquinones, 1-amino-2-methyl-4-arylaminoanthraquinones, 1-amino-4-bromoanthraquinone 2-sulfonic acid esters and sulfonamides, and bis-(1-amino-4-bromoanthraquinone) sulfonamides, and investigated them in preparations of rat NTPDase1, 2, and 3 using a capillary electrophoresis assay. Several 1-amino-2-sulfo-4-ar(alk)ylaminoanthraquinone derivatives inhibited E-NTPDases in a concentration-dependent manner. The 2-sulfonate group was found to be required for inhibitory activity, since 2-methyl-substituted derivatives were inactive. 1-Amino-2-sulfo-4-p-chloroanilinoanthraquinone (18) was identified as a nonselective competitive blocker of NTPDases1, 2, and 3 (Ki 16–18 μM), while 1-amino-2-sulfo-4-(2-naphthylamino)anthraquinone (21) was a potent inhibitor with preference for NTPDase1 (Ki 0.328 μM) and NTPDase3 (Ki 2.22 μM). Its isomer, 1-amino-2-sulfo-4-(1-naphthylamino)anthraquinone (20), was a potent and selective inhibitor of rat NTPDase3 (Ki 1.5 μM)

Topics: Original Article
Publisher: Springer Netherlands
OAI identifier: oai:pubmedcentral.nih.gov:2721768
Provided by: PubMed Central

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Citations

  1. (2005). A capillary electrophoresis method for the characterization of ecto-nucleoside triphosphate diphosphohydrolases (NTPDases) and the analysis of inhibitors by in-capillary enzymatic microreaction. Purinergic Signalling 1:349–358
  2. (1948). Acidic derivatives of anthraquinone. I. Influence of substituents in the phenylamine radical of anthraquinone derivatives on their properties.
  3. (1997). An ecto-ATPase and an ecto-ATP diphosphohydrolase are expressed in rat brain.
  4. (1933). Anthraquinone derivatives.
  5. (1999). CD39-L4 is a secreted human apyrase, specific for the hydrolysis of nucleoside diphosphates.
  6. (2007). CD39/ ectonucleoside triphosphate diphosphohydrolase 1 provides myocardial protection during cardiac ischemia/reperfusion injury.
  7. (2003). Characterization of an ectonucleoside triphosphate diphosphohydrolase 1 activity in alkaline phosphatase-depleted rat osseous membranes: possible functional involvement in the calcification process.
  8. (2005). Cloning and characterization of the ecto-nucleotidase NTPDase3 from rat brain: predicted secondary structure and relation to other members of the E-NTPDase family and actin. Purinergic Signalling 1:259–270 106 Purinergic Signalling
  9. (2007). Cloning, purification, and identification of the liver canalicular ecto-ATPase as NTPDase8.
  10. (2008). Combinatorial synthesis of anilinoanthraquinone derivatives and evaluation as non-nucleotidederived P2Y2 receptor antagonists.
  11. (2003). Determination of native oligomeric state and substrate specificity of rat NTPDase1 and NTPDase2 after heterologous expression in Xenopus oocytes.
  12. (2002). Differential catalytic properties and vascular topography of murine nucleoside triphosphate diphosphohydrolase 1 (NTPDase1) and NTPDase2 have implications for thromboregulation.
  13. (2006). Ectonucleotidases in the nervous system.
  14. (2001). Ectonucleotidases: some recent developments and a note on nomenclature.
  15. (2004). Effect of the ectoATPase inhibitor, ARL 67156, on the bovine chromaffin cell response to ATP.
  16. (2007). Eltzschig HK
  17. (2003). Enzymatic and transcriptional regulation of human ecto-ATPase/E-NTPDase 2.
  18. (2007). Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression.
  19. (2000). Extracellular metabolism of ATP and other nucleotides.
  20. (1999). Functional characterization of rat ecto-ATPase and ecto-ATP diphosphohydrolase after heterologous expression in CHO cells.
  21. (2006). Immunolocalization of ecto-nucleoside triphosphate for modulation of multiple homeostatic systems including feeding and sleep-wake behaviours.
  22. (2000). Inhibition of ecto-apyrase and ectoATPase by pyridoxal phosphate-related compounds.
  23. (1996). Inhibition of ecto-ATPase by PPADS, suramin and reactive blue in endothelial cells, C6 glioma cells and RAW 264.7 macrophages.
  24. (1995). Inhibition of purified chicken gizzard smooth muscle ecto-ATPase by P2 purinoceptor antagonists.
  25. (1999). Inhibition of rat parotid ectoATPase activity.
  26. (2003). Members of the acid blue 129 family as potent and selective P2Y-receptor antagonists. Drug Dev Res 59:63–71
  27. (1996). Modulation of purinergic neurotransmission by ecto-ATPase.
  28. (2006). Molecular cloning and characterization of expressed human ectonucleoside triphosphate diphosphohydrolase 8 (E-NTPDase8) and its soluble extracellular domain.
  29. (2006). Noise-induced up-regulation of NTPDase3 expression in the rat cochlea: implications for auditory transmission and cochlear protection.
  30. (2000). Novel inhibitors of nucleoside triphosphate diphosphohydrolases: chemical synthesis and biochemical and pharmacological characterizations.
  31. (2006). Nucleoside triphosphate diphosphohydrolase-2 (NTPDase2/ CD39L1) is the dominant ectonucleotidase expressed by rat astrocytes.
  32. (2007). Nucleotide metabolizing ecto-enzymes in Walker 256 tumor cells: molecular identification, kinetic characterization and biochemical properties.
  33. (1996). P2-purinoceptor antagonists: II. Blockade of P2-purinoceptor subtypes and ecto-nucleotidases by compounds related to Evans blue and trypan blue.
  34. (1996). P2-purinoceptor antagonists: III. Blockade of P2-purinoceptor subtypes and ecto-nucleotidases by compounds related to suramin.
  35. (1998). P2-receptor antagonists: IV. Blockade of P2-receptor subtypes and ecto-nucleotidases by compounds related to reactive blue 2. Naunyn Schmiedebergs Arch Pharmacol 357:111–120
  36. (1994). Pharmacological analysis of ecto-ATPase inhibition: evidence for combined enzyme inhibition and receptor antagonism in P2X-purinoceptor ligands.
  37. (2007). Physiology and pathophysiology of purinergic neurotransmission.
  38. (2006). Polyoxometalates—a new class of potent ecto-nucleoside triphosphate diphosphohydrolase (NTPDase) inhibitors.
  39. (2003). Purification and characterization of NTPDase1 (ecto-apyrase) and NTPDase2 (ecto-ATPase) from porcine brain cortex synaptosomes.
  40. (2002). Purine signaling and potential new therapeutic approach: possible outcomes of NTPDase inhibition.
  41. (2007). Rapid and efficient microwave-assisted copper(0)-catalyzed Ullmann coupling reaction. Org Lett 9:1271–
  42. (1995). Reactive red 2: a P2y-selective purinoceptor antagonist and an inhibitor of ecto-nucleotidase.
  43. (2007). Role of P2 purinergic receptors in synaptic transmission under normoxic and ischaemic conditions in the CA1 region of rat hippocampal slices. Purinergic Signalling 3:203–219 Purinergic Signalling
  44. (2008). Selective nucleoside triphosphate diphosphohydrolase-2 (NTPDase2) inhibitors: nucleotide mimetics derived from uridine-5′-carboxamide. J Med Chem,
  45. (2007). Specificity of the ecto-ATPase inhibitor ARL 67156 on human and mouse ectonucleotidases.
  46. (2001). The C-terminal cysteine-rich region dictates specific 104 Purinergic Signalling (2009) 5:91–106catalytic properties in chimeras of the ectonucleotidases NTPDase1 and NTPDase2.
  47. (2006). The E-NTPDase family of ectonucleotidases: structure-function relationships and pathophysiological significance. Purinergic Signalling 2:409–
  48. (2007). The ectonucleotidases alkaline phosphatase and nucleoside triphosphate diphosphohydrolase 2 are associated with subsets of progenitor cell populations in the mouse embryonic, postnatal and adult neurogenic zones.
  49. (1936). The effect of alkyl groups on the properties of anthraquinone and fluorescein dyes.
  50. (2006). The structure of the nucleoside triphosphate diphosphydrolases (NTPDases) as revealed by mutagenic and computational modelin analyses. Purinergic Signalling 2:379–389
  51. (1999). Two novel families of ectonucleotidases: molecular structures, catalytic properties and a search for function. Trends Pharmacol Sci

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