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Chemical Compound Review

Melarsen     disodiumN2-(4- dioxidoarsorylphenyl)- 1,3,5...

Synonyms: AG-F-25228, LS-21701, CTK4H5717, AC1L52RE, 3599-28-8, ...
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Disease relevance of NSC 10894

 

High impact information on NSC 10894

  • When bloodstream Trypanosoma brucei are incubated with either melarsen oxide or the 2,3-dimercaptopropanol adduct of melarsen oxide (melarsoprol), Mel T is the only arsenical derivative detectable in acid-soluble extracts of the cells [3].
  • Analysis of the uptake of pentamidine and other diamidines in melarsen-resistant trypanosomes in vitro and in vivo, which also show differential levels of resistance to these compounds in vivo, indicated that P2 transport was altered in these cells and that accumulation of these drugs was markedly reduced [4].
  • Uptake of diamidine drugs by the P2 nucleoside transporter in melarsen-sensitive and -resistant Trypanosoma brucei brucei [4].
  • In a rodent model of central nervous system infection, five of six mice survived for more than 180 days (5 mg/kg intravenously), indicating a sufficient melarsen oxide penetration across the blood-brain barrier [5].
  • This discrepancy is not an effect of drug metabolism since over-expression of MRPA alone conferred resistance to melarsoprol and its principle metabolite, melarsen oxide, in vitro [1].
 

Biological context of NSC 10894

  • The human enzyme is inhibited by melarsen oxide in a competitive manner with a Ki of 23.7 microM, whereas the filarial GRs are inhibited in two stages: an immediate partial inactivation followed by a time-dependent stage with saturable pseudo-first-order kinetics [6].
  • MelT, an adduct of melarsen oxide and dihydrotrypanothione which is a competitive inhibitor of the disulfide binding site of trypanothione reductase, confers protection against Triostam [7].
  • We have developed a strategy for the characterization of protein folding intermediates that combines selective modification of bis-cysteinyl thiol groups with melarsen oxide (MEL), chromatographic separation and mass spectrometric characterization of the resulting protein derivatives [8].
 

Anatomical context of NSC 10894

 

Associations of NSC 10894 with other chemical compounds

 

Gene context of NSC 10894

 

Analytical, diagnostic and therapeutic context of NSC 10894

  • Either melarsen oxide or a yet-undiscovered active metabolite is irreversibly bound to proteins, as shown by ultrafiltration, precipitation experiments, and atomic absorption spectroscopy [5].

References

  1. The role of Trypanosoma brucei MRPA in melarsoprol susceptibility. Alibu, V.P., Richter, C., Voncken, F., Marti, G., Shahi, S., Renggli, C.K., Seebeck, T., Brun, R., Clayton, C. Mol. Biochem. Parasitol. (2006) [Pubmed]
  2. Relative efficacy of melarsen oxide compared with mel Cy (Cymelarsan) when used in combination with difluoromethylornithine in the treatment of trypanosomiasis of the central nervous system. Jennings, F.W. Trans. R. Soc. Trop. Med. Hyg. (1992) [Pubmed]
  3. Trypanothione is the primary target for arsenical drugs against African trypanosomes. Fairlamb, A.H., Henderson, G.B., Cerami, A. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
  4. Uptake of diamidine drugs by the P2 nucleoside transporter in melarsen-sensitive and -resistant Trypanosoma brucei brucei. Carter, N.S., Berger, B.J., Fairlamb, A.H. J. Biol. Chem. (1995) [Pubmed]
  5. Investigations of the metabolites of the trypanocidal drug melarsoprol. Keiser, J., Ericsson, O., Burri, C. Clin. Pharmacol. Ther. (2000) [Pubmed]
  6. Differential susceptibility of filarial and human erythrocyte glutathione reductase to inhibition by the trivalent organic arsenical melarsen oxide. Müller, S., Walter, R.D., Fairlamb, A.H. Mol. Biochem. Parasitol. (1995) [Pubmed]
  7. Trypanothione reductase from Leishmania donovani. Purification, characterisation and inhibition by trivalent antimonials. Cunningham, M.L., Fairlamb, A.H. Eur. J. Biochem. (1995) [Pubmed]
  8. Structural characterization of monomeric folding intermediates of recombinant human macrophage-colony stimulating factor beta (rhM-CSFbeta) by chemical trapping, chromatographic separation and mass spectrometric peptide mapping. Peter Happersberger, H., Cowgill, C., Glocker, M.O. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. (2002) [Pubmed]
  9. The interaction of arsenical drugs with dihydrolipoamide and dihydrolipoamide dehydrogenase from arsenical resistant and sensitive strains of Trypanosoma brucei brucei. Fairlamb, A.H., Smith, K., Hunter, K.J. Mol. Biochem. Parasitol. (1992) [Pubmed]
  10. Biosynthesis and uptake of thiamine (vitamin B1) in bloodstream form Trypanosoma brucei brucei and interference of the vitamin with melarsen oxide activity. Stoffel, S.A., Rodenko, B., Schweingruber, A.M., Mäser, P., de Koning, H.P., Schweingruber, M.E. Int. J. Parasitol. (2006) [Pubmed]
  11. Characterisation of melarsen-resistant Trypanosoma brucei brucei with respect to cross-resistance to other drugs and trypanothione metabolism. Fairlamb, A.H., Carter, N.S., Cunningham, M., Smith, K. Mol. Biochem. Parasitol. (1992) [Pubmed]
  12. Effects of various metabolic conditions and of the trivalent arsenical melarsen oxide on the intracellular levels of fructose 2,6-bisphosphate and of glycolytic intermediates in Trypanosoma brucei. Van Schaftingen, E., Opperdoes, F.R., Hers, H.G. Eur. J. Biochem. (1987) [Pubmed]
 
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