Advertisement

Iron-Complexing Bioactive Polymers

  • Anthony Winston

Abstract

Polymers bearing functional groups possessing a special ability to bind iron are under consideration as potential drugs for treating iron overload caused by iron poisoning and by diseases such as Cooley’s anemia. The functional groups of greatest current interest include hydroxamic acids, catechols, and phenols. Model compounds include naturally occurring desferrioxamine-B, a tris-hydroxamic acid, and enterobactin, a tris-catecholate. Attachment of the functional groups to polymers enhances the iron chelating ability by the “chelate effect” caused by the polymers holding the groups in close proximity to each other. The determination of the stability constants of a series of hydroxamic acid polymers has confirmed the existence of the chelate effects in such cases. The in vivo activities of the polymers were determined by means of a mouse screen designed to measure the ability of the drug to remove iron from iron-overloaded mice. Bioassays of only a few polymers of the hydroxamic acid type have been reported. The polymers removed iron from iron-overloaded mice to an extent approaching that of the standard desferrioxamine-B. Additional polymers of the hydroxamic acid type, as well as catechol and phenolic types, are under consideration or are being tested. These results should be available soon.

Keywords

Stability Constant Iron Overload Iron Chelator Hydroxamic Acid Iron Complex 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    H. S. Waxman and E. B. Brown, Clinical usefulness of iron chelating agents, in: Progress in Hematology (E. B. Brown and C. V. Moore, eds.), Vol. VI, pp. 338–373, Grune & Stratton (1969).Google Scholar
  2. 2.
    A. I. Chernoff, Blood,J.Hematol 14, 899 (1959).Google Scholar
  3. 3.
    T. F. Necheles, D. M. Allen, and H. E. Finkel, Clinical Disorders of Hemoglobin Structure and Synthesis, Meredith Corporation, New York (1969).Google Scholar
  4. 4.
    D. J. Weatherall, The iron loading anemias, in: Development of Iron Chelators for Clinical Use (A. E. Martell, W. F. Anderson, and D. G. Badman, eds.), pp. 3–12, Elsevier/North Holland, New York (1981).Google Scholar
  5. 5.
    J. C. Chang and Y. W. Kan, Proc. Natl. Acad. Sci. U.S.A. 76, 2886 (1979).CrossRefGoogle Scholar
  6. 6.
    R. F. Trecartin, S. A. Leibhaber, J. C. Chang, K. Y. Lee, Y. W. Kan, M. Furbetta, A. Anguis, and A. Cao,J.Clin. Invest. 68, 1012–17 (1981).CrossRefGoogle Scholar
  7. 7.
    B. Modell, Advances in the use of iron chelating agents for the treatment of iron overload, in: Progress in Hematology (E. B. Brown, ed.), Vol. XI, pp. 267–312, Grune & Stratton, New York (1979).Google Scholar
  8. 8.
    W. F. Anderson, Iron chelation in the treatment of Cooley’s anemia, in: Inorganic Chemistry in Biology and Medicine (A. E. Martell, ed.), pp. 251–261, American Chemical Society Symposium Series 140, Washington, D.C. (1980).CrossRefGoogle Scholar
  9. 9.
    E. C. Zaino and R. H. Roberts, eds., Chelation Therapy in Chronic Iron Overload, Symposia Specialists Inc., Miami, Fla. (1977).Google Scholar
  10. 10.
    Assessment of Cooley’s Anemia Reseach and Treatment, DHEW Publication No. (NIH) 79–1653 (March 1979).Google Scholar
  11. 11.
    W. F. Anderson and M. C. Hiller, eds., Development of Iron Chelators for Clinical Use, U.S. Department of Health, Education and Welfare, DHEW Publication No. (NIH) 77–994, Bethesda, Md. (1975).Google Scholar
  12. 12.
    D. J. Weatherall and J. B. Clegg, The Thalassaemia Syndromes, 3rd Edition, Blackwell, Oxford (1981).Google Scholar
  13. 13.
    J. B. Neilands, J. Am. Chem. Soc. 74, 4846 (1952).CrossRefGoogle Scholar
  14. 14.
    S. J. Rogers, R. A. Warren, and J. B. Neilands, Nature 200, 167 (1963).CrossRefGoogle Scholar
  15. 15.
    W. Keller-Schierlein and B. Maurer, Helv. Chim. Acta 52, 603 (1969).CrossRefGoogle Scholar
  16. 16.
    H. Bickel, G. E. Hall, W. Keller-Schierlein, V. Prelog, and E. Vischer, Helv. Chim. Acta 43, 2129 (1960).CrossRefGoogle Scholar
  17. 17.
    H. Bickel, H. Keberle, and E. Vischer, Helv. Chim. Acta 46, 1385 (1963).CrossRefGoogle Scholar
  18. 18.
    V. Prelog and A. Walser, Helv. Chim. Acta 45, 631 (1962).CrossRefGoogle Scholar
  19. 19.
    W. Keller-Schierlein, V. Prelog, and Z. Zahner, Siderochrome (Naturliche Eisen(III)-trihydroxamat-Komplexe), in: Fortschritte der Chemie Organischer Naturstoffe (L. Zechmeister, ed.), pp. 279–322, Springer-Verlag, Wien (1964).Google Scholar
  20. 20.
    J. B. Neilands, Microbial iron transport compounds (siderochromes), in: Inorganic Biochemistry (G. Eichhorn, ed.), pp. 167–202, Elsevier, Amsterdam (1973).Google Scholar
  21. 21.
    J. B. Neilands, Struct. Bond. 11, 145 (1972).CrossRefGoogle Scholar
  22. 22.
    J. B. Neilands, Struct. Bond. 1, 59 (1966).CrossRefGoogle Scholar
  23. 23.
    H. Maehr, Pure Appl. Chem. 28, 603 (1971).CrossRefGoogle Scholar
  24. 24.
    J. B. Neilands, Microbial iron transport compounds (siderophores), in: Development of Iron Chelators for Clinical Use (W. F. Anderson and M. C. Hiller, eds.), pp. 5–44, U.S. Department of Health, Education and Welfare, DHEW Publication No. (NIH) 77–994, Bethesda, Md. (1975).Google Scholar
  25. 25.
    J. B. Neilands, Microbial iron transport compounds (siderophores) as chelating agents, in: Development of Iron chelators for Clinical Use (A. E. Martell, W. F. Anderson, and D. G. Badman, eds.), pp. 13–31, EIsevier/North-Holland, Amsterdam (1981).Google Scholar
  26. 26.
    S. Moeschlin and U. Schnider, New Engl. J. Med. 269, 57 (1963).CrossRefGoogle Scholar
  27. 27.
    R. D. Propper and D. G. Nathan, The use of desferoxamine and “the pump”, in: Chelation Therapy in Chronic Iron Overload (E. C. Zaino and R. H. Roberts, eds.), pp. 17–35, Symposia Specialists, Miami, Fla. (1977).Google Scholar
  28. 28.
    C. G. Pitt, G. Gupta, W. E. Estes, H. Rosenkrantz, J. J. Metterville, A. L. Crumbliss, R. A. Palmer, K. W. Nordquest, K. A Sprinkle Hardy, D. R. Whitcomb, B. R. Byers, J. E. L. Arceneaux, C. G. Gaines, and C. V. Sciortino, J. Pharm. Exp. Therap. 208, 12 (1979).Google Scholar
  29. 29.
    R. W. Grady, C. M. Peterson, R. L. Jones, J. H. Graziano, K. K. Bharguva, V. A. Berdoukas, G. Kokkini, D. Loukopoulous, and A. Cerami, J. Pharm. Exp. Therap. 209, 342 (1979).Google Scholar
  30. 30.
    H. Lossen, Justus Liebigs Ann. Chem. 150, 314 (1869).CrossRefGoogle Scholar
  31. 31.
    D. D. Coffman, U.S. Patent 2,402,604 (1946): Chem. Abstr. 40, 529429 (1946).Google Scholar
  32. 32.
    E. Cocea, M. Grigoras, and M. Tutoveanu, Bull. Inst. Politeh. Iasi 11, 159 (1965)Google Scholar
  33. 32a.
    E. Cocea, M. Grigoras, and M. Tutoveanu, Chem. Abstr. 64, 19,800a (1966).Google Scholar
  34. 33.
    M. Vrancken and G. Smets,J.Polym. Sci. 14, 521 (1954).CrossRefGoogle Scholar
  35. 34.
    J. P. Cornaz and H. Deuel, Experientia 10, 137 (1954).CrossRefGoogle Scholar
  36. 35.
    J. P. Cornaz, K. Hutschneker, and H. Deuel, Helv. Chim. Acta 40, 2015 (1957).CrossRefGoogle Scholar
  37. 36.
    G. Petrie, D. Locke, and C. E. Meloan, Anal. Chem. 37, 919 (1965).CrossRefGoogle Scholar
  38. 37.
    A. Winston, C. R. Jenkins, W. Lerdthusnee, and S. J. Masten, Development and Evaluation of Ion-Exchange Resins for Removal of Specific Metals in Water Treatment Information Report 17, Water Research Institute, West Virginia University, Morgantown, West Va. (1981).Google Scholar
  39. 38.
    W. Kern and R. C. Schulz, Angew. Chem. 69, 153 (1957).CrossRefGoogle Scholar
  40. 39.
    M. Hatano, Y. Nose, T. Nozawa, and S. Kambara, Kogyo Kagaku Zasshi 69, 571 (1966)CrossRefGoogle Scholar
  41. 39a.
    M. Hatano, Y. Nose, T. Nozawa, and S. Kambara, Chem. Abstr. 65, 15532g (1966).Google Scholar
  42. 40.
    A. Peden, H. Smith, and E. J. Vickers, Brit. Patent 887,175 (1962); Chem. Abstr. 57, 3630a (1962).Google Scholar
  43. 41.
    F. Becke and C. Mutz, Chem. Ber. 98, 1322 (1965).CrossRefGoogle Scholar
  44. 42.
    L. W. Jones and L. Neuffer, J. Am. Chem. Soc. 39, 659 (1917).CrossRefGoogle Scholar
  45. 43.
    H. Smith, British Patent 852,176 (1960); Chem. Abstr. 55, 9284i (1961).Google Scholar
  46. 44.
    G. M. Gasparini and S. Vomero, Com. Naz. Energy Nucl., RT/CHI, 70, 25 (1970)Google Scholar
  47. 44a.
    G. M. Gasparini and S. Vomero, Chem. Abstr. 74, 112752f (1971).Google Scholar
  48. 45.
    F. Schouteden, Makromol. Chem. 27, 246 (1958).CrossRefGoogle Scholar
  49. 46.
    F. Schouteden, Chim. Ind. (Paris) 79, 749 (1958)Google Scholar
  50. 46a.
    F. Schouteden, Chem. Abstr. 52, 21116e (1958).Google Scholar
  51. 47.
    F. Schouteden and J. A. Herbots, Belgian Patent 560,782 (1958); Chem. Abstr. 53, 5739f (1959).Google Scholar
  52. 48.
    F. Schouteden,J.Soc. Dyers Colour. 75, 309 (1959).Google Scholar
  53. 49.
    F. Vernon and H. Eccles, Anal. Chim. Acta 82, 369 (1976).CrossRefGoogle Scholar
  54. 50.
    F. Vernon and H. Eccles, Anal. Chim. Acta 83, 187 (1976).CrossRefGoogle Scholar
  55. 51.
    C. A. Fetscher, U.S. Patent 3,154,499 (1964); Chem. Abstr. 62, 4882d (1965).Google Scholar
  56. 52.
    C. A. Fetscher and S. A. Lipowski, U.S. Patent 3,345,344 (1967); Chem. Abstr. 67, 109273a (1967).Google Scholar
  57. 53.
    R. S. Ramirez and J. D. Andrade, J. Macromol. Sci., Chem. A7, 1035 (1973).Google Scholar
  58. 54.
    R. S. Ramirez and J. D. Andrade, Polym. Prepr., Am. Chem. Soc, Div. Polym. Chem. 15, 391 (1974).Google Scholar
  59. 55.
    R. S. Ramirez and J. D. Andrade, J. Macromol. Sci., Chem. A10, 309 (1976).Google Scholar
  60. 56.
    G. Schwarzenbach and K. Schwarzenbach, Helv. Chim. Acta 46, 1390 (1963).CrossRefGoogle Scholar
  61. 57.
    G. Anderegg, F. L’Eplattenier, and G. Schwarzenbach, Helv. Chim. Acta 46, 1400 (1963).CrossRefGoogle Scholar
  62. 58.
    G. Anderegg, F. L’Eplattenier, and G. Schwarzenbach, Helv. Chim. Acta 46, 1409 (1963).CrossRefGoogle Scholar
  63. 59.
    A. Winston and E. T. Mazza,J.Polym. Sci., Polym. Chem. Ed. 13, 2019 (1975).CrossRefGoogle Scholar
  64. 60.
    A. Winston and G. R. McLaughlin, J. Polym. Sci., Polym. Chem. Ed. 14, 2155 (1976).CrossRefGoogle Scholar
  65. 61.
    A. Winston and D. Kirchner, Macromolecules 11, 597 (1978).CrossRefGoogle Scholar
  66. 62.
    D. V. P. R. Vasaprasad, J. Rosthauser, and A. Winston,J.Polym. Sci., Polym. Chem. Ed. 22, 2131 (1984).CrossRefGoogle Scholar
  67. 63.
    M. I. Dawson, I. S. Cloudsdale, C. S. Tyson, S. Le Valley, and W. R. Harris, Progress toward the synthesis of polymerically bound chelating agents for iron(III) and the development of a new assay method for determining iron chelator effectiveness, in: Development of Iron Chelators for Clinical Use (A. E. Martell, W. F. Anderson, and D. G. Badman, eds.), pp. 201–209, Elsevier/North-Holland, Amsterdam (1981).Google Scholar
  68. 64.
    D. J. Dawson, D. O. Otteson, P. C. Wang, and R. E. Wingard, Jr., Macromolecules 11, 320 (1978).CrossRefGoogle Scholar
  69. 65.
    J. R. Pollack and J. B. Neilands, Biochem. Biophys. Res. Commun. 38, 989 (1970).CrossRefGoogle Scholar
  70. 66.
    W. R. Harris, C. J. Carrano, S. R. Cooper, S. R. Sofen, A. E. Avdeef, J. V. McArdle, and K. E. Raymond,J.Am. Chem. Soc. 101, 6097 (1979).CrossRefGoogle Scholar
  71. 67.
    K. N. Raymond, V. L. Pecoraro, and F. L. Weitl, Design of new chelating agents, in: Development of Iron Chelators for Clinical Use (A. E. Martell, W. F. Anderson, and D. G. Badman, eds.), pp. 165–187, Elsevier/North-Holland, Amsterdam (1981).Google Scholar
  72. 68.
    M. C. Venuti, W. H. Rastetter, and J. B. Neilands,J.Med. Chem. 22, 123 (1979).CrossRefGoogle Scholar
  73. 69.
    W. H. Rastetter, T. J. Erickson, and M. C. Venuti,J.Org. Chem. 46, 3579 (1981).CrossRefGoogle Scholar
  74. 70.
    M. I. Dawson, R. L. -S. Chan, I. S. Cloudsdale, and W. R. Harris, Tetrahedron Lett. 22, 2739 (1981).CrossRefGoogle Scholar
  75. 71.
    D. L. Fair, Iron Binding Catechol Polymers, Dissertation submitted in partial fulfillment of Ph.D. degree, West Virginia University, Morgantown, W. Va. (1981).Google Scholar
  76. 72.
    E. B. Brown, Candidate chelating drugs: Where do we stand?, in: Development of Iron Chelators for Clinical Use (A. E. Martell, W. F. Anderson, and D. G. Badman, eds.), pp. 47–59, Elsevier/North-Holland, Amsterdam (1981).Google Scholar
  77. 73.
    A. Jacobs, Screening for iron chelating drugs, in: Development of Iron Chelators for Clinical Use (A. E. Martell, W. F. Anderson, and D. G. Badman, eds.), pp. 39–46, Elsevier/North-Holland, Amsterdam (1981).Google Scholar
  78. 74.
    C. G. Pitt and A. E. Martell, The design of chelating agents for the treatment of iron overload, in: Inorganic Chemistry in Biology and Medicine (A. E. Martell, ed.), pp. 279–312, American Chemical Society Symposium Series 140, Washington, D.C. (1980).CrossRefGoogle Scholar
  79. 75.
    A. E. Martell, The design and synthesis of chelating agents, in: Development of Iron Chelators for Clinical Use (A. E. Martell, W. F. Anderson, and D. G. Badman, eds.), pp. 67–104, Elsevier/North-Holland, Amsterdam (1981).Google Scholar
  80. 76.
    K. N. Raymond, W. R. Harris, C. J. Carrano and F. L. Weitl, The synthesis, thermodynamic behavior and biological properties of metal-iron-specific sequestering agents for iron, in: Inorganic Chemistry in Biology and Medicine (A. E. Martell, ed.). pp. 313–332, American Chemical Society Symposium Series 140, Washington, D.C. (1980).CrossRefGoogle Scholar
  81. 77.
    W. R. Harris and K. N. Raymond, J. Am. Chem. Soc. 101, 6534 (1979).CrossRefGoogle Scholar
  82. 78.
    T. Emery, Amer. Scient. 70, 626, 1982.Google Scholar
  83. 79.
    S. Pollack, P. Aisen, F. D. Lasky, and G. Vanderhoff, Brit. J. Haematol. 34, 231 (1976).CrossRefGoogle Scholar
  84. 80.
    G. P. White, A. Jacobs, R. W. Grady, and A. Cerami, Brit. J. Haematol. 33, 486 (1976).CrossRefGoogle Scholar
  85. 81.
    G. P. White, A. Jacobs, R. W. Grady, and A. Cerami, Blood 48, 923 (1976).Google Scholar
  86. 82.
    R. W. Grady and A. Jacobs, The screening of potential iron chelating drugs, in: Development of Iron Chelators for Clinical Use (A. E. Martell, W. F. Anderson, and D. G. Badman, eds.), pp. 133–164, Elsevier/North-Holland, Amsterdam (1981).Google Scholar
  87. 83.
    A. Cerami, R. W. Grady, and C. M. Peterson, New iron chelators, in: Chelation Therapy in Chronic Iron Overload (E. C. Zaino and R. H. Roberts, eds.), pp. 37–52, Symposia Specialists Inc., Miami, Fla. (1981).Google Scholar
  88. 84.
    C. G. Pitt, Structure and activity relationships of iron chelating drugs, in: Development of Iron Chelators for Clinical Use (A. E. Martell, W. F. Anderson, and D. G. Badman, eds.), pp. 105–131, Elsevier/North-Holland, Amsterdam (1981).Google Scholar
  89. 85.
    A. Winston, J. Rosthauser, D. Fair, J. Bapasola, and W. Lerdthusnee, Design of polymeric iron chelators for treating iron overload in Cooley’s anemia, in: Biological Activities of Polymers (C. E. Carraher, Jr. and C. G. Gebelein, eds.), pp. 107–117, American Chemical Society Symposium Series 186, Washington, D.C. (1982).CrossRefGoogle Scholar
  90. 86.
    M. R. Summers, A. Jacobs, D. Tudway, P. Perera, and C. Ricketts,J.Haematol. 42, 547 (1979).CrossRefGoogle Scholar
  91. 87.
    R. D. Propper and D. G. Nathan, Use of desferrioxamine and “the pump”, in: Chelation Therapy in Chronic Iron Overload (E. C. Zaino and R. H. Roberts, eds.), pp. 17–35, Symposia Specialists Inc., Miami, Fla. (1981).Google Scholar
  92. 88.
    J. W. Rosthauser and A. Winston, Macromolecules 14, 538 (1981).CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1985

Authors and Affiliations

  • Anthony Winston
    • 1
  1. 1.Department of ChemistryWest Virginia UniversityMorgantownUSA

Personalised recommendations