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Iron Chelation Therapy pp 167–184Cite as

Structure-Activity Relationships Among Desazadesferrithiocin Analogues

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Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 509))

Abstract

Iron, a transition metal, represents 5% of the earth’s crust. It exists in a variety of oxidation states ranging from the zero-valent metal itself to Fe(VI), occurring in such diverse forms as iron disulfide (FeS2, “fool’s gold”), iron oxides, including magnetite (Fe304), and hemoglobin. However, the Fe(II) and Fe(III) oxidation states (Equation 1) are of the most relevance in the present discussion.

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References

  1. Ortiz de Montellano PR ed Cytochrome p450 - structure, metabolism, and biochemistry. New York: Plenum; 1986.

    Google Scholar 

  2. Sahlin M, Petersson L, Graslund A, et al. Magnetic interaction between the tyrosyl free radical and the antiferromagnetically coupled iron center in ribonucleotide reductase. Biochemistry 1987;26:5541–5548.

    Article  CAS  Google Scholar 

  3. Raymond KN, Carrano CJ. Coordination chemistry and microbial iron transport. Acc Chem Res 1979;12:183–190.

    Article  CAS  Google Scholar 

  4. Halliwell B. Iron, oxidative damage, and chelating agents. Bergeron RJ, Brittenham GM, eds. The development of iron chelators for clinical use. Boca Raton, CRC, 1994,33–56.

    Google Scholar 

  5. Britigan BE, Pou S, Rosen GM, Lilleg DM, Buettner GR. Hydroxyl radical is not a product of the reaction of xanthine oxidase and xanthine. The confounding problem of adventitious iron bound to xanthine oxidase. JBiol Chem 1990;265:17533–17538.

    CAS  Google Scholar 

  6. Bergeron R.I. Iron: A controlling nutrient in proliferative processes. Trends Biochem Sci 1986;11:133-136.

    Article  CAS  Google Scholar 

  7. Bickel H, Hall GE, Keller-Schierlein W, et al. Metabolic products of actinomycetes. XXVII. Constitutional formula of ferrioxamine B. Rely Chim Acta 1960;43:2129–2138.

    Article  CAS  Google Scholar 

  8. Bickel H, Bosshardt R, Gäumann E, et al. Metabolic products of actinomycetes. XXVI. Isolation and properties of ferrioxamines A to F, representing new sideramine compounds. Helv Chim Acta 1960;43:2118–2128.

    Article  CAS  Google Scholar 

  9. Kunze B, Trowitzsch-Kienast W, Höfle G, Reichenbach H. Nannochelins A, B, and C, new iron-chelating compounds from Nannocystis exedens (myxobacteria). JAntibiot 1992;45:147–150.

    CAS  Google Scholar 

  10. Atkin CL, Neilands JB. Rhodotorulic acid, a diketopiperazine dihydroxamic acid with growth-factor activity. I. Isolation and characterization. Biochemistry 1968;7:3734–3739.

    Article  CAS  Google Scholar 

  11. Tait GH. The identification and biosynthesis of siderochromes formed by Micrococcus denitrificans. Biochem J 1975;146:191–204.

    CAS  Google Scholar 

  12. Peterson T, Neilands JB. Revised structure of a catecholamide spermidine siderophore from Paracoccus denitrificans. Tetrahedron Lett 1979:4805–4808.

    Google Scholar 

  13. Griffiths GL, Sigel SP, Payne SM, Neilands JB. Vibriobactin, a siderophore from Vibrio cholerae. JBiol Chem 1984; 259:383–385.

    CAS  Google Scholar 

  14. Martell AE, Motekaitis RJ, Sun Y, Clarke ET. Ligand design of chelating agents effective in the coordination of Fe(III) and for the removal of iron in cases of iron overload. Bergeron RJ, Brittenham GM, eds. The development of iron chelators for clinical use. Boca Raton, CRC, 1994,329–351.

    Google Scholar 

  15. Anderegg G, L’Eplattenier F, Schwarzenbach G. Hydroxamate complexes. II. Application of the pH method. Helv Chim Acta 1963;46:1400–1408.

    Article  CAS  Google Scholar 

  16. Harris WR, Carrano CJ, Cooper SR, et al. Coordination chemistry of microbial iron transport compounds. XIX. Stability constants and electrochemical behavior of ferric enterobactin and model complexes. JAm Chem Soc 1979;101:6097–6104.

    Article  CAS  Google Scholar 

  17. Motekaitis RJ, Martell AE. Stabilities of the iron(III) chelates of 1,2-dimethyl-3-hydroxy-4-pyridinone and related ligands. Inorg Chim Acta 1991;183:71–80.

    Article  CAS  Google Scholar 

  18. Clarke ET, Martell AE. Stabilities of 1,2-dimethyl-3-hydroxy-4-pyridinone chelates of divalent and trivalent metal ions. Inorg Chim Acta 1992;191:56–63.

    Article  CAS  Google Scholar 

  19. Neilands JB, Peterson T, Leong SA. High affinity iron transport in microorganisms. Iron (III) coordination compounds of the siderophores agrobactin and parabactin. Martell AE, ed. Inorganic chemistry in biology and medicine. Vol. 140. American Chemical Society symposia. Washington, D.C., American Chemical Society, 1980,263–278.

    Google Scholar 

  20. Harris WR, Carrano CJ, Raymond KN. Spectrophotometric determination of the proton-dependent stability constant of ferric enterobactin. JAm Chem Soc 1979;101:2213–2214.

    Article  CAS  Google Scholar 

  21. Avdeef A, Sofen SR, Bregante TL, Raymond KN. Coordination chemistry of microbial iron transport compounds. 9. Stability constants for catechol models of enterobactin. J Am Chem Soc 1978;100:53625370.

    Google Scholar 

  22. Anderegg G, Räber M. Metal complex formation of a new siderophore desferrithiocin and of three related ligands. J Chem Soc, Chem Commun 1990:1194–1196.

    Google Scholar 

  23. Hahn FE, McMurry TJ, Hugi A, Raymond KN. Coordination chemistry of microbial iron transport. 42. Structural and spectroscopic characterization of diastereomeric Cr(III) and Co(III) complexes of desferriferrithiocin. JAm Chem Soc 1990;112:1854–1860.

    Article  CAS  Google Scholar 

  24. L’Eplattenier F, Murase I, Martell AE. New multidentate ligands. VI. Chelating tendencies of N,N-di(2hydroxybenzyl)ethylenediamine-N,N-diacetic acid. JAm Chem Soc 1967; 89:837-843.

    Article  Google Scholar 

  25. Pitt CG, Gupta G, Estes WE, et al. The selection and evaluation of new chelating agents for the treatment of iron overload. J Pharmacol Exp Ther 1979;208:12-18.

    CAS  Google Scholar 

  26. Kontoghiorghes GJ, Sheppard L, Chambers S. New synthetic approach and iron chelating studies of 1alkyl-2-methyl-3-hydroxypyrid-4-ones. Arzneimittelforschung 1987;37:1099–1102.

    CAS  Google Scholar 

  27. Bergeron RJ, Liu Z-R, McManis JS, Wiegand J. Structural alterations in desferrioxamine compatible with iron clearance in animals. JMed Chem 1992;35:4739–4744.

    Article  CAS  Google Scholar 

  28. Harris WH, Raymond KN. Ferric ion sequestering agents. 3. The spectrophotometric and potentiometric evaluation of two new enterobactin analogs: 1,5,9-N,N,N“-tris(2,3- dihydroxybenzoyl)cyclotriazatridecane and 1,3,5-N,N,N’-tris(2,3- dihydroxybenzoyl)triaminomethylbenzene. J Am Chem Soc 1979;101:65346541.

    Article  CAS  Google Scholar 

  29. Motekaitis RJ, Sun Y, Martell AE. N,N-bis(pyridoxyl)ethylenediamine-N,N-diacetic acid (PLED) and N,N-bis(2-hydroxy-5-sulfobenzyl)ethylenediamine-N,N-diacetic acid (SHBED). Inorg Chim Acta 1989;159:29–39.

    Article  CAS  Google Scholar 

  30. Fahey JL, Rath CE, Princiotto JV, Brick IB, Rubin M. Evaluation of trisodium calcium diethylenetriaminepentaacetate in iron storage disease. JLab Clin Med 1961;57:436–449.

    CAS  Google Scholar 

  31. Smith RS. Iron excretion in thalassemia major after administration of chelating agents. Br Med J 1962;2:1577–1580.

    Article  CAS  Google Scholar 

  32. Wöhler F. The treatment of haemochromatosis with desferrioxamine. Acta Haematol 1963;30:65–87.

    Article  Google Scholar 

  33. Pippard MJ, Jackson MJ, Hoffman K, Petrou M, Modell CB. Iron chelation using subcutaneous infusions of diethylene triamine penta-acetic acid (DTPA). Scand J Haematol 1986;36:466–472.

    Article  CAS  Google Scholar 

  34. Wonke B, Hoffbrand AV, Aldouri M, et al. Reversal of desferrioxamine induced auditory neurotoxicity during treatment with Ca-DTPA. Arch Dis Child 1989;64:77–82.

    Article  CAS  Google Scholar 

  35. Olivieri NF, Brittenham GM. Iron-chelating therapy and the treatment of thalassemia. Blood 1997;89:739761.

    Google Scholar 

  36. Pippard MJ. Desferrioxamine-induced iron excretion in humans. Bailleres Clin Haematol 1989;2:323–343.

    Article  CAS  Google Scholar 

  37. Whitten CF, Gibson GW, Good MH, Goodwin JF, Brough AJ. Studies in acute iron poisoning. I. Desferrioxamine in the treatment of acute iron poisoning: Clinical observations, experimental studies, and theoretical considerations. Pediatrics 1965;36:322–335.

    CAS  Google Scholar 

  38. Athanasiou A, Shepp MA, Necheles TF. Anaphylactic reaction to desferrioxamine. Lancet 1977;2:616.

    Article  Google Scholar 

  39. Shalit M, Tedeschi A, Miadonna A, Levi-Schaffer F. Desferal (desferrioxamine)- a novel activator of tissue-type mast cells. JAllergy Clin Immunol 1991;88:854–860.

    Article  CAS  Google Scholar 

  40. Bousquet J, Navarro M, Robert G, Aye P, Michel FB. Rapid desensitization for desferrioxamine anaphylactoid reactions. Lancet 1983;2:859–860.

    Article  CAS  Google Scholar 

  41. Miller KB, Rosenwasser LJ, Bessette JAM, Beer DJ, Rocklin RE. Rapid desensitisation for desferrioxamine anaphylactic reaction. Lancet 1981;1:1059.

    Article  CAS  Google Scholar 

  42. Olivieri NF, Buncic JR, Chew E, et al. Visual and auditory neurotoxicity in patients receiving subcutaneous deferoxamine infusions. N Engl J Med 1986;314:869–873.

    Article  CAS  Google Scholar 

  43. Nouel O, Voisin PM, Vaucel J, Dartois Hoguin M, Le Bris M. [Yersinia enterocolitica septicemia associated with idiopathic hemochromatosis and deferoxamine therapy. A case]. Presse Med 1991;20:1494–1496.

    CAS  Google Scholar 

  44. Bentur Y, McGuigan M, Koren G. Deferoxamine (desferrioxamine). New toxicities for an old drug. Drug Saf 1991;6:37–46.

    Article  CAS  Google Scholar 

  45. Naegeli H-U, Zähner H. Metabolites of microorganisms. Part 193. Ferrithiocin. Heiv Chim Acta 1980;63:1400–1406.

    Article  CAS  Google Scholar 

  46. Bergeron RJ, Wiegand J, Dionis JB, et al. Evaluation of desferrithiocin and its synthetic analogues as orally effective iron chelators. JMed Chem 1991;34:2072–2078.

    Article  CAS  Google Scholar 

  47. Bergeron RJ, Streiff RR, Wiegand J, et al. A comparative evaluation of iron clearance models. Ann N Y Acad Sci 1990;612:378–393.

    Article  CAS  Google Scholar 

  48. Bergeron RI, Streiff RR, Creary EA, et al. A comparative study of the iron-clearing properties of desferrithiocin analogues with desferrioxamine B in a Cebus monkey model. Blood 1993;81:2166–2173.

    CAS  Google Scholar 

  49. Bergeron RJ, Liu CZ, McManis JS, et al. The desferrithiocin pharmacophore. JMed Chem 1994;37:1411–1417.

    Article  CAS  Google Scholar 

  50. Bergeron RJ, Wiegand J, Wollenweber M, et al. Synthesis and biological evaluation of naphthyldesferrithiocin iron chelators. JMed Chem 1996;39:1575–1581.

    Article  CAS  Google Scholar 

  51. Bergeron RJ, Wiegand J, Weimar WR, et al. Desazadesmethyldesferrithiocin analogues as orally effective iron chelators. JMed Chem 1999;42:95–108.

    Article  CAS  Google Scholar 

  52. Bergeron RJ, Wiegand J, McManis JS, et al. Effects of C-4 stereochemistry and C-4’ hydroxylation on the iron clearing efficiency and toxicity of desferrithiocin analogues. JMed Chem 1999;42:2432–2440.

    Article  CAS  Google Scholar 

  53. Bergeron RJ, Weimar WR, Wiegand J. Pharmacokinetics of orally administered desferrithiocin analogs in Cebus apella primates. Drug Metab Dispos 1999;27:1496–1498.

    CAS  Google Scholar 

  54. Brittenham GM. Pyridoxal isonicotinoyl hydrazone (PIH): Effective iron chelation after oral administration. Ann N YAcad Sci 1990;612:315–326.

    Article  CAS  Google Scholar 

  55. Shetty B, Badr M, Melethil S. Evaluation of hepatic metabolism of salicylic acid in perfused rat liver. J Pharm Sci 1994;83:607–608.

    Article  CAS  Google Scholar 

  56. McMahon TF, Stefanski SA, Wilson RE, et al. Comparative acute nephrotoxicity of salicylic acid, 2,3dihydroxybenzoic acid, and 2,5-dihydroxybenzoic acid in young and aged Fischer 344 rats. Toxicology 1991;66:297–311.

    Article  CAS  Google Scholar 

  57. Bergeron RJ, Wiegand J, Ratliff Thompson K, Weimar WR. The origin of the differences in (R)- and (S)desmethyldesferrithiocin:Iron-clearing properties. Ann N YAcad Sci 1998;850:202–216.

    Article  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Medicinal Chemistry, University of Florida, Florida, 32610, USA, USA

    Raymond J. Bergeron

Authors
  1. Raymond J. Bergeron
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  2. Jan Wiegand
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  3. James S. McManis
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  4. William R. Weimar
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  5. Guangfei Huang
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Editor information

Editors and Affiliations

  1. Hebrew University School of Medicine, Jerusalem, Israel

    Chaim Hershko

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© 2002 Kluwer Academic/Plenum Publishers, New York

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Bergeron, R.J., Wiegand, J., McManis, J.S., Weimar, W.R., Huang, G. (2002). Structure-Activity Relationships Among Desazadesferrithiocin Analogues. In: Hershko, C. (eds) Iron Chelation Therapy. Advances in Experimental Medicine and Biology, vol 509. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0593-8_9

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  • DOI: https://doi.org/10.1007/978-1-4615-0593-8_9

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-0-306-46785-1

  • Online ISBN: 978-1-4615-0593-8

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