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Iron chelating agents with clinical potential

Published online by Cambridge University Press:  05 December 2011

R. C. Hider ,
S. Singh  and
J. B. Porter
R. C. Hider
Affiliation:
Department of Pharmacy, King's College London, Manresa Road, London SW3 6LX, U.K.
S. Singh
Affiliation:
Department of Pharmacy, King's College London, Manresa Road, London SW3 6LX, U.K.
J. B. Porter
Affiliation:
Department of Haematology, University College Hospital Medical School, Chenies Mews, London WC1, U.K.
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Synopsis:

Iron is a critically important metal for a wide variety of cellular events. The element holds this central position by virtue of its facile redox chemistry and the high affinity of both redox states (iron II and iron III) for oxygen. These same properties also render iron toxic when levels exceed the normal binding capacity of the cell. As a result of this potential toxicity, selective iron chelators are finding an important role in the treatment of iron overload associated with many forms of thalassaemia. In addition, they appear to have potential in treating situations where a local increase in iron concentration causes an unfavourable pathology, for instance, in reperfused tissue (heart disease and stroke) and in Parkinsonian brain. There is also evidence that iron chelators may minimise the toxicity of paraquat and the side effects of bleomycin and doxorubicin.

Non-haem iron enzymes can also be inhibited by iron chelators and consequently such enzymes as ribonucleotide reductase and lipoxygenase can be selectively inhibited. Such inhibitory action is being investigated for the treatment of malaria, neoplastic disease, psoriasis and asthma.

Recent developments in these areas are discussed in the present overview.

Type
Research Article
Information
Proceedings of the Royal Society of Edinburgh, Section B: Biological Sciences , Volume 99 , Issue 1-2: The Advancement of Drug Discovery , 1992 , pp. 137 - 168
Copyright
Copyright © Royal Society of Edinburgh 1992

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References

Agid, Y. 1991. Parkinson's Disease: pathophysiology. The Lancet I, 1321–7.CrossRefGoogle Scholar
Akkerman, M. A. J., Neijman, E. W. J. F., Wijmenga, S. S., Hilbers, C. W. & Bermel, W. 1990. Studies of the solution structure of the bleomycin A2–-iron(II)-carbon monoxide complex by means of two-dimensional NMR spectroscopy and distance geometry calculations. Journal of the American Chemical Society 112, 7462–74.CrossRefGoogle Scholar
Anden, N. E., Fuxe, K., Hamberger, B. & Hokfelt, T. 1966. A quantitative study of the nigro-neostriatal dopamine neuron system in the rat. Acta Physiologica Scandinavica 67, 306–12.CrossRefGoogle ScholarPubMed
Andrews, F., Morris, C. J., Kondratowicz, G. & Blake, D. R. 1987. The effect of iron chelation on inflammatory joint disease. Annals of Rheumatic Disease 46, 327–33.CrossRefGoogle ScholarPubMed
Atherton, D. J., Wells, R. S., Laurent, M. R. & Williams, Y. F. 1980. Razoxane (IRCF 159) in the treatment of psoriasis. British Journal of Dermatology 102, 307–17.CrossRefGoogle Scholar
Aust, S. D. 1988. Sources of iron for lipid peroxidation in biological systems. In Oxygen radicals and tissue injury, pp. 27–33, ed. Halliwell, B. Maryland: Federation of American Societies for Experimental Biology.Google Scholar
Aust, S. D. & White, B. C. 1985. Iron chelation prevents tissue injury following ischaemia. Advances in Free Radical Biology and Medicine 1, 1–17.CrossRefGoogle Scholar
Bartlett, A. N., Hoffbrand, A. V. & Kontoghiorghes, G. J. 1990. Long-term trial with the oral iron chelator l,2-dimethyl-3-hydroxypyrid-4-one (L1). British Journal of Haematology 76, 301–4.CrossRefGoogle Scholar
Beckman, J. S., Beckman, T. W., Chen, J., Marshall, P. A. & Freeman, B. A. 1990. Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proceedings of the National Academy of Sciences, USA 87, 1620–4.CrossRefGoogle ScholarPubMed
Becton, D. L. & Bryles, P. 1988. Deferoxamine inhibition of human neuroblastoma viability and proliferation. Cancer Research 48, 7189–92.Google ScholarPubMed
Bergeron, R. J. 1986. Iron: a controlling nutrient in proliferative processes. Trends in Biochemical Sciences 11, 133–6.CrossRefGoogle Scholar
Bergeron, R. J. & Ingeno, M. J. 1987. Microbial iron chelator-induced cell cycle synchronisation in L1210 cells: potential in combination chemotherapy. Cancer Research 47, 6010–16.Google ScholarPubMed
Bergeron, R. J., Gavanaugh, P. F., Kline, S. J., Hughes, R. G., Elliot, G. T. & Porter, C. W. 1984. Antineoplastic and antiherpetic activity of spermidine catecholamide iron chelators. Biochemical and Biophysical Research Communications 121, 848–54.CrossRefGoogle ScholarPubMed
Berman, H. M. & Young, P. R. 1981. The interaction of intercalating drugs with nucleic acids. Annual Reviews in Biophysics and Bioengineering 10, 87–114.CrossRefGoogle ScholarPubMed
Blake, D. R. & Bacon, P. A. 1981. Synovial fluid ferritin in rheumatoid arthritis: an index or cause of inflammation. British Medical Journal 282, 189.CrossRefGoogle ScholarPubMed
Blake, D. R., Gallagher, P. J., Potter, A. R., Bell, M. J. & Bacon, P. 1984. The effect of synovial iron on the progression of rheumatoid disease. A histological assessment of patients with early rheumatoid disease. Arthritis and Rheumatism 27, 495–501.CrossRefGoogle Scholar
Blake, D. R., Winyard, P., Lunec, J., Williams, A., Good, P. A., Crewes, S. J., Gutteridge, J. M. C., Rowley, D., Halliwell, B., Cornish, A. & Hider, R. C. 1985. Cerebral and ocular toxicity induced by deferioxamine. Quarterly Journal of Medicine 56, 345–55.Google Scholar
Blatt, J. & Stitely, S. 1987. Anti-neuroblastoma activity of deferioxamine in human cell lines. Cancer Research 47, 1749–50.Google Scholar
Cashman, J. R. 1985. Leukotriene biosynthesis inhibitors. Pharmaceutical Research 253–61.CrossRefGoogle Scholar
Cho, H., Ueda, M., Tamaoka, M., Hamaguchi, M., Aisaka, K., Kiso, Y., Inove, T., Ognion, R., Taksuoka, T., Ishihara, T., Noguchi, T., Morita, I. & Murota, S. 1991. Novel caffeic acid derivatives: extremely potent inhibitors of 12-lipoxygenase. Journal of Medicinal Chemistry 34, 1503–05.CrossRefGoogle ScholarPubMed
Cory, J. G., Lasater, L. & Sato, A. 1981. Effect of iron-chelating agents on inhibitors of ribonucleotide reductase. Biochemical Pharmacology 30, 979–84.CrossRefGoogle ScholarPubMed
Crichton, R. R. 1991. Inorganic biochemistry of iron metabolism. London: Ellis Horwood.Google Scholar
Cross, C. E., Warren, D., Gerriets, J. E., Wilson, D. W., Halliwell, B. & Last, J. A. 1985. Deferoxamine injection does not affect bleomycin-induced lung fibrosis in rats. Journal of Laboratory and Clinical Medicine 106, 433–8.Google Scholar
Davies, M. J., Donker, R., Dunster, C. A., Gee, C. A., Jones, S. & Willson, R. L. 1987. Deferoxamine (Desferal) and superoxide free radicals: formation of an enzyme-damaging nitroxide. Biochemical Journal 246, 725–9.CrossRefGoogle ScholarPubMed
Dexter, D. T., Wells, F. R., Agid, F., Agid, Y., Lees, A. J., Jenner, P. & Marsden, C. D. 1987. Increased nigral iron content in postmortem Parkinsonian brain. The Lancet II, 1219–20.CrossRefGoogle Scholar
Dexter, D. T., Wells, F. R., Lees, A. J., Agid, F., Agid, Y., Jenner, P. & Marsden, C. D. 1989a. Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson' disease. Journal of Neurochemistry 52, 1830–6.CrossRefGoogle Scholar
Dexter, D. T., Carter, C. J., Wells, F. R., Javoy-Agid, F., Agid, Y., Lees, A., Jenner, P. & Marsden, C. D. 1989b. Basal lipid peroxidation in substantia nigra is increased in Parkinson's disease. Journal of Neurochemistry 52, 381–9.CrossRefGoogle ScholarPubMed
Dezza, L., Cazzola, M., Danova, M., Carlo-Stella, C., Bergamaschi, G., Brugnatelli, S., Invernizzi, R., Mazzini, G., Riccardi, A. & Ascari, E. 1987. Effects of deferioxamine inhibition of human neuroblastoma viability and proliferation. Cancer Research 48, 7189–92.Google Scholar
Dolence, E. K., Minnick, A. A., Lin, C. E. & Miller, M. J. 1991. Synthesis and Siderophore and Antibacterial Activity of N5-Acetyl-N5-hydroxy-L-ornithine-derived Siderophore-β-lactam conjugates: iron-transport-mediated drug delivery. Journal of Medicinal Chemistry 34, 968–78.CrossRefGoogle ScholarPubMed
Estrov, Z., Tawa, A., Wang, X., Dube, I., Sulh, H., Cohen, A., Gelfand, E. & Freedman, M. H. (1987). In vitro and in vivo effects of deferoxamine in neonatal acute leukemia. Blood 69, 757–61.CrossRefGoogle ScholarPubMed
Foa, P., Maiolo, A. T., Lombardi, L., Villa, L. & Polli, E. E. 1986. Inhibition of proliferation of human leukaemic cell lines by deferoxamine. Scandinavian Journal of Haematology 36, 107–10.CrossRefGoogle ScholarPubMed
Ford, G. C., Harrison, P. M., Rice, D. W., Smith, J. M. A., Treffry, A., White, J. L. & Yariv, J. 1984. Ferritin: design and formation of an iron-storage molecule. Philosophical Transactions of the Royal Society, London B304, 551–65.Google Scholar
Funk, M. O., Carroll, R. T., Thompson, J. F., Sands, R. H. & Dunham, W. R. 1990. Role of iron in lipoxygenase catalysis. Journal of American Chemical Society 112, 5375–6.CrossRefGoogle Scholar
Ganeshaguru, K., Hoffbrand, A. V., Grady, R. W., Cerami, A. 1980. Effect of various iron chelating agents on DNA synthesis in human cells. Biochemical Pharmacology 29, 1275–9.CrossRefGoogle ScholarPubMed
Gelvan, D., Berg, E., Saltman, P. & Samuni, A. 1990. Time-dependent modifiers of ferric-adriamycin. Biochemical Pharmacology 39, 1289–95.CrossRefGoogle Scholar
Gianni, L., Zweier, J. L., Levy, A. & Myers, C. E. 1985. Characterisation of the cycle of iron-mediated electron transfer from adriamycin to molecular oxygen. Journal of Biological Chemistry 260, 6820–9.CrossRefGoogle ScholarPubMed
Ginsburg, H. & Stein, W. D. 1987. Biophysical analysis of novel transport pathways induced in red blood cell membranes. Journal of Membrane Biology 96, 1–10.CrossRefGoogle ScholarPubMed
Gordeuk, V. R., Thuma, P. E., Brittenham, G. M., Zulu, S., Simwanza, G., Mhangu, A., Flesch, G. & Parry, D. 1991. Iron chelation with deferoxamine B in adults with asymptomatic Plasmodium falciparum Parasitemia. Blood 79, 308–12.CrossRefGoogle Scholar
Gordonsmith, R. H., Brooke-Taylor, S., Smith, L. L. & Cohen, G. M. 1983. Structural requirements of compounds to inhibit pulmonary diamine accumulation. Biochemical Pharmacology 32, 3701–9.CrossRefGoogle ScholarPubMed
Green, C. J., Gower, J. D., Healing, G., Cotterill, L. A., Fuller, B. J. & Simpkin, S. 1989. The importance of iron, calcium and free radicals in reperfusion injury: an overview of studies in ischaemic rabbit kidneys. Free Radical Research Communications 7, 255–64.CrossRefGoogle ScholarPubMed
Green, C. J., Healing, G., Simpkin, S., Lunec, J. and Fuller, B. J. 1986. Deferoxamine reduces susceptibility to lipid peroxidation in rabbit kidneys subjected to warm ischaemia and reperfusion. Comparative Biochemistry and Physiology 85B, 113–117.Google Scholar
Hallgren, B. & Sourander, P. 1958. The non-haemin iron in the cerebral cortex of Alzheimer's Disease. Journal of Neurochemistry 3, 41–54.CrossRefGoogle Scholar
Halliwell, B. & Gutteridge, J. M. C. 1989. Free radicals in biology and medicine, 2nd edn. Oxford: Clarendon Press.Google Scholar
Harding, C., Heuser, J. & Stahl, P. 1983. Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes. Journal of Cell Biology 97, 329–39.CrossRefGoogle ScholarPubMed
Hartmann, A., Fielder, H. P. & Braun, V. 1979. Uptake and conversion of the antibiotic albomycin by Escherichia coli K-12. European Journal of Biochemistry 99, 517–24.CrossRefGoogle ScholarPubMed
Harvey, A. R., Clarke, B. J., Chui, D. H. K., Kean, W. F. & Buchanan, M. W. 1983. Anaemia associated with rheumatoid disease. Inverse correlation between erythropoiesis and both IgM and Rheumatoid Factor levels. Arthritis and Rheumatism 26, 28–34.CrossRefGoogle ScholarPubMed
Healing, G., Gower, J., Fuller, B. & Green, C. 1990. Intracellular iron distribution. An important determinant of reperfusion damage to rabbit kidneys. Biochemical Pharamaology 39, 1239–45.CrossRefGoogle Scholar
Hearse, D. J., Manning, A. S., Downey, J. M. & Yellon, D. M. 1986. Xanthine oxidase: a critical mediator of myocardial injury during ischaemia and reperfusion? Acta Physiologica Scandinavica 548, 67–78.Google Scholar
Hernandez, L. A., Grisham, M. B. & Granger, D. N. 1987. A role for iron in oxidant-mediated ischaemic injury to intestinal microvasculture. American Journal of Physiology 253, G49–G53.Google Scholar
Hershko, C., Grady, R. W. & Link, G. 1984. Phenolic ethylenediamine derivatives: a study of orally effective iron chelators. Journal of Laboratory and Clinical Medicine 103, 337–46.Google ScholarPubMed
Hershko, C. H., Peto, T. E. A. & Weatherall, D. J. 1988. Iron and infection. British Journal of Haematology 296, 660–4.Google ScholarPubMed
Hershko, C., Theanacho, E. N., Spira, D. T., Peter, H. H., Dobbin, P. & Hider, R. C. 1991. The effect of N-alkyl modification on the antimalarial activity of 3-hydroxypyridin-4-one oral iron chelators. Blood 11, 637–43.CrossRefGoogle Scholar
Hewitt, S. D., Hider, R. C., Sarpong, P., Morris, C. J. & Blake, D. 1989. Investigation of the anti-inflammatory properties of hydroxpyridinones. Annals of Rheumatic Diseases 48, 382–8.CrossRefGoogle Scholar
Hider, R. C. 1984. Siderophore mediated absorption of iron. Structure and Bonding 38, 25–87.CrossRefGoogle Scholar
Hider, R. C. & Hall, A. D. 1991a. Iron chelating agents in medicine, the application of bidentate hydroxypyridin-4-ones. In Perspectives on bioinorganic chemistry, Vol. 1, eds Hay, R. W. Dilworth, J. R. & Nolan, K. B. London: JAI Press.Google Scholar
Hider, R. C. & Hall, A. D. 1991b. Clinically useful chelators of tripositive elements. Progress in Medicinal Chemistry 28, 41–173.CrossRefGoogle ScholarPubMed
Hider, R. C., Mohd-Nor, A. R., Silver, J., Morrison, I. E. G. & Rees, L. V. C. 1981. Model compounds for microbial iron-transport compounds. Journal of the Chemical Society, Dalton Transactions 609–22.Google Scholar
Hider, R. C., Singh, S., Porter, J. B. & Huehns, E. R. 1990. The development of hydroxypyridin-4-ones as orally active iron chelators. Annals New York Academy of Sciences 612, 327–38.CrossRefGoogle ScholarPubMed
Horton, J. J. & Wells, R. S. 1983. Razoxane: a review of 6 years' therapy in psoriasis. British Journal of Dermatology 109, 669–73.CrossRefGoogle ScholarPubMed
Horton, J. J., MacDonald, D. M. & Wells, R. S. 1983. Epitheliomas in patients receiving razoxane therapy for psoriasis. British Journal of Dermatology 109, 675–8.CrossRefGoogle ScholarPubMed
Hoyes, K. P., Hider, R. C. & Porter, J. B. 1992. Cell cycle synchronisation and growth inhibition by 3-hydroxypyridin-4-one iron chelators in leukaemia cell lines. Cancer Research (in press).Google Scholar
Huebers, H. & Finch, C. A. 1987. The physiology of transferrin and transferrin receptors. Physiological Reviews 67, 520–82.CrossRefGoogle ScholarPubMed
Jackson, M. J., Brenton, D. P. & Modell, B. 1983. DTPA in the management of iron overload in thalassaemia. Journal of Inherited Metabolic Diseases 6 (Suppl. 2), 97–8.CrossRefGoogle Scholar
Jackson, W. P., Islip, P. J., Kneen, G., Pugh, A. & Wates, P. J. 1988. Acetohydroxamic acids as potent, selective orally active 5-lipoxygenase inhibitors. Journal of Medicinal Chemistry 31, 499–500.CrossRefGoogle ScholarPubMed
Kemal, C., Louis-Flamberg, P., Krupinski-Olsen, R. & Shorter, A. L. 1987. Reduction inactivation of soybean lipoxygenase 1 by catechols: a possible mechanism for regulation of lipoxygenase activity. Biochemistry 26, 1064–72.CrossRefGoogle ScholarPubMed
Kerdesky, F. A. J., Holms, J. H., Schmidt, S. P., Dyer, R. D. & Carter, G. W. 1985. Eicosatetraenehydroxamates: inhibitors of 5-lipoxygenase. Tetrahedron Letters 2143–5.CrossRefGoogle Scholar
Klein, J., Damani, L. A., Chung, D., Epemolu, O., Olivieri, N. & Koren, G. 1991. A high-performance liquid chromatographic method for the measurement of the iron chelator l,2-dimethyl-3-hydroxy-pyridin-4-one in human plasma. Therapeutic Drug Monitoring 13, 51–4.CrossRefGoogle Scholar
Komara, J. S., Nayini, N. R., Bialick, H. A., Indrien, R. J., Evans, A. T., Garritano, A. M., Hoehner, T. J., Jacobs, W. A., Huang, R. R., Krause, G. S., White, B. C. & Aust, S. D. 1986. Brain iron delocalisation and lipid peroxidation following cardiac arrest. Annals of Emergency Medicine 15, 384–9.CrossRefGoogle Scholar
Kontoghiorghes, G. J., Bartlett, A. N., Hoffbrand, A. V., Goddard, J. G., Sheppard, L., Barr, J. & Nortey, P. 1990. Long-term trial with the oral iron chelator l,2-dimethyl-l-3-hydroxypyrid-4-one (LI). British Journal of Haematology 76, 295–300.CrossRefGoogle Scholar
Lakhani, S., Davidson, R. N., Hiwaizi, F. & Marsden, R. A. 1984. Razoxane and leukaemia. The Lancet II, 288–9.CrossRefGoogle Scholar
Lau, E. H., Cerny, E. A., Wright, B. J. & Rahman, Y. E. 1983. Improvement of iron removal from the reticuloendothelial system by liposome encapsulation of N,N′-diacetic acid (HBED). Journal of Laboratory and Clinical Medicine 101, 806–16.Google Scholar
Lawson, A. A. H., Owen, E. T. & Mowat, A. G. 1983. Nature of anaemia in rheumatoid disease. Storage of iron in rheumatoid disease. Annals of the Rheumatic Diseases 26, 552–9.CrossRefGoogle Scholar
Lederman, H. M., Cohen, A., Lee, J. W. W., Freedman, M. H. & Gelland, E. W. 1984. Deferoxamine: a reversible S-phase inhibitor of human lymphocyte proliferation. Blood 64, 748–53.CrossRefGoogle ScholarPubMed
Levin, V. A. 1980. Relationship of octanol/water partition coefficient and molecular weight to rat brain capillary permeability. Journal of Medicinal Chemistry 23, 682–4.CrossRefGoogle ScholarPubMed
Martell, A. E., Matekaitis, R. J. & Clarke, E. T. 1986. Synthesis of N,N′-di(2-hydroxybenzyl)ethylenediamine-N,N′-diacetic acid (HBED) derivatives. Canadian Journal of Chemistry 64, 449–56.CrossRefGoogle Scholar
May, W. S. & Cuatrecasas, P. 1985. Transferrin receptor: its biological significance. Journal of Membrane Biology 88, 205–15.CrossRefGoogle ScholarPubMed
Mentasti, E., Pelizzetti, E. & Saini, G. 1976. Interactions of Fe(III) with adrenaline, L-dopa and other catechol derivatives. Journal of Inorganic and Nuclear Chemistry 38, 785–8.CrossRefGoogle Scholar
Menter, A. & Barker, J. N. W. N. 1991. Psoriasis in practice. The Lancet II, 231–4.CrossRefGoogle Scholar
Moran, R. E. & Straus, M. J. 1980. Synchronisation of L1210 leukemia with hydroxyurea infusion and the effect of subsequent pulse dose chemotherapy. Cancer Treatment Therapy 64, 81–6.Google ScholarPubMed
Morita, I. & Murota, S. 1987. Role of 12-lipoxygenase products of arachidionic acid on platelet aggregation. Advances in Prostglandin, Thromboxane, and Leukotriene Research 17, 219–26.Google Scholar
Moses, K., Harris, A. L. & Durkawz, B. W. 1988. Adenosine diphosphoribosyltransferase inhibitors can protect against or potentiate the cytotoxicity of S phase acting drugs. Biochemical Pharmacology 37, 2155–60.CrossRefGoogle ScholarPubMed
Muirden, K. D. 1966. Ferritin in synovial cells in patients with rheumatoid arthritis. Annals of theRheumatic Diseases 25, 387–401.CrossRefGoogle ScholarPubMed
Munro, H. & Linder, M. C. 1978. Ferritin: biosynthesis and role in iron metabolism. Physiology Reviews 58, 317–96.CrossRefGoogle ScholarPubMed
Myers, C., Gianni, L., Zweier, J., Muindi, J., Sinha, B. K. & Eliot, H. 1986. Role of iron in adriamycin biochemistry. Federation Proceedings 45, 2792–7.Google ScholarPubMed
Nakao, J., Koshihara, Y., Ito, H., Murota, S. & Chang, W. C. 1985. Enchancement of endogenous production of 12-L-hydroxy-5,8,10,14-eicosatetraenoic acid in aortic smooth muscle cells by platelet derived growth factor. Life Sciences 37, 1435–42.CrossRefGoogle Scholar
Nelson, M. J. 1988. Catecholate complexes of ferric soybean lipoxygenase 1. Biochemistry 27, 4273–8.CrossRefGoogle Scholar
Nolan, K. B., Murphy, T., Hermanns, R. D., Rahoo, H. & Creighton, A. 1990. Chelating agents as anti-tumour pro-drug razoxane. Inoganica Chemica Acta 168, 283–8.CrossRefGoogle Scholar
Nordlund, P., Sjöberg, B. M., & Eklund, H., 1990. Three-dimensional structure of the free radical structure of the free radical protein of ribonucleotide reductase. Nature 345, 593–8.CrossRefGoogle ScholarPubMed
Porter, J. B., & Huehns, E. R., 1989. The toxic effects of deferoxamine. Baillière's Clinical Haematology 2, 459–74.CrossRefGoogle Scholar
Nordlund, P., Huehns, E. R., & Hider, R. C., 1989. The development of iron chelating drugs. Baillière's Clinical Haematology 2, 257–92.Google Scholar
Nordlund, P., Morgan, J., Hoyes, K. P., Burke, L. C., Huehns, E. R., & Hider, R. C., 1990. Relative oral efficacy and acute toxicity of hydroxypyridin-4-one iron chelators in mice. Blood 76, 2389–96.Google Scholar
Raventos-Suarez, C., Pollack, S., & Nagel, R. L., 1982. Plasmodium falciparum: Inhibition in vitro growth by deferoxamine. American Journal of Tropical Medicine and Hygiene 31, 919–22.CrossRefGoogle Scholar
Reddy, B. R., Kloner, R. A., & Przyklenk, K., 1989. Early treatment with deferoxamine limits myocardial ischaemic/reperfusion injury. Free Radical Biology and Medicine 7, 45–52.CrossRefGoogle Scholar
Reichard, P., & Ehrenberg, A., 1983. Ribonucleotide reductase – a radical enzyme. Science 221, 514–19.CrossRefGoogle ScholarPubMed
Robins-Browne, R. M., & Prpic, J. K., 1985. Effects of iron and deferoxamine on infections with Yersinia enterocolitica. Infectious Immunology 47, 774–9.CrossRefGoogle ScholarPubMed
Senator, G. B., & Muirden, K. D., 1968. Concentration of iron in synovial membrane, synovial fluid and serum in rheumatoid arthritis and other joint diseases. Annals of Rheumatic Diseases 27, 49–53.CrossRefGoogle ScholarPubMed
Silley, P., Griffiths, J. W., Monsey, D., & Harris, A. M., 1990. Mode of action of GR69153, a novel catechol-substituted cephalosporin and its interaction with the ton B-dependent iron transport system. Anti-Microbial Agents and Chemotherapy 34, 1806–08.CrossRefGoogle Scholar
Singh, S., Hider, R. C., & Porter, J. B., 1990. A direct method for quantification of non-transferrin-bound iron. Analytical Biochemistry 186, 320–3.CrossRefGoogle ScholarPubMed
Sotomatsu, A., Nakano, M., & Hirai, S., 1990. Phospholipid peroxidation induced by the catechol-Fe3+(Cu2+) complex: a possible mechanism of nigrostriatal cell damage. Archives of Biochemistry and Biophysics 283, 334–41.CrossRefGoogle ScholarPubMed
Streater, M., Taylor, P. D., Hider, R. C., & Porter, J. B., 1990. Novel 3-hydroxy-2(lH)-pyridinones. Synthesis, iron(III)-chelating properties and biological activity. Journal of Medicinal Chemistry 33, 1749–55.CrossRefGoogle Scholar
Sugiura, Y., Suzuki, T., Kuwahara, J., & Tanaka, H., 1982. On the mechanism of hydrogen peroxide-, superoxide-, and ultraviolet light-induced DNA changes of inactive bleomycin-Iron(III) complex. Biochemical and Biophysical Research Communications 105, 1511–18.CrossRefGoogle Scholar
Summers, J. B., Mazdiyasni, H., Holms, J. H., Ratajczyk, J. D., Dyer, R. D., & Carter, G. W., 1987. Hydroxamic acid inhibitors of 5-lipoxygenase. Journal of Medicinal Chemistry 30, 574–80.CrossRefGoogle ScholarPubMed
Summers, J. B., Gunn, B. P., Martin, J. G., Mazdiyasni, H., Stewart, A. O., Young, P. R., Goetze, A. M., Bousko, J. B., Dyer, R. D., Brooks, D. W., & Carter, G. W., 1988. Orally active hydroxamic acid inhibitors of leukotriene biosynthesis. Journal of Medicinal Chemistry 31, 3–5.CrossRefGoogle ScholarPubMed
Summers, J. B., Kim, K. H., Mazdiyasni, H., Holms, J. H., Ratajczyk, J. D., Stewart, A. O., Dyer, R. D., & Carter, G. W., 1990. Journal of Medicinal Chemistry 33, 992–8.CrossRefGoogle Scholar
Taylor, G. W., & Clarke, S. R., 1986. The leukotriene biosynthetic pathway: a target for pharmacological attack. Trends in Pharmacological Sciences 6, 100–03.CrossRefGoogle Scholar
Thomas, C. E., & Aust, S. D., 1986. Release of iron from ferritin by cardiotoxic anthracycline antibiotics. Archives of Biochemistry and Biophysics 248, 684–9.CrossRefGoogle ScholarPubMed
Thorstensen, K., 1988. Hepatocytes and reticulocytes have different mechanisms for the uptake of iron from transferrin. Journal of Biological Chemistry 263, 16837–41.CrossRefGoogle ScholarPubMed
Turner, S. R., Tainer, J. A., & Lynn, W. S., 1975. Biogenesis of chemotactic molecules by the arachidonate lipoxygenase system of platelets. Nature 257, 680–1.CrossRefGoogle ScholarPubMed
van der Kraaij, A. M. M., van Eijk, H. G., & Koster, J. F., 1989. Prevention of postischaemic cardiac injury by the orally active iron chelator l, 2-dimethyl-3-hydroxy-4-pyridone (LI) and the antioxidant(+)-cyanidanol-3. Circulation 80, 158–64.CrossRefGoogle Scholar
van der Waal, N. A. A., Smith, L. L., van Oirschot, F. L. M., & van Asbeck, B. S., 1992. Effect of Iron Chelators on Paraquat Toxicity in Rats and Alveolar Type II Cells. American Reviews of Respiratory Diseases 145, 180–6.CrossRefGoogle Scholar
Vile, G. F., Winterbourn, C. C., & Sutton, H. C., 1987. Radical-driven Fenton reactions: studies with paraquat, adriamycin, and anthraquinone-6-sulfonate and citrate, ATP, ADP, and pyrophosplate iron chelates. Archives of Biochemistry and Biophysics 259, 616–26.CrossRefGoogle ScholarPubMed
Ward, H. E., Hicks, M., Nicholson, A., & Berend, N., 1988. Deferoxamine infusion does not inhibit bleomycin-induced lung damage in the rat. American Reviews in Respiratory Diseases 137, 1356–9.CrossRefGoogle Scholar
Washington, J. A., Jones, R. N., Allen, S. D., Gerlack, E. H., Koontz, F. P., Murray, P. R., Pfaller, M. A., & Erwin, M. E., 1991. In vitro comparison of GR69153, a novel catechol-substituted cephalosporin, with ceftazidime, and ceftriaxone against 5,203 recent clinical isolates. Antimicrobial Agents and Chemotherapy 35, 1508–11.CrossRefGoogle Scholar
Weatherall, D. J., & Clegg, J. B., 1981. The thalassaemia syndromes. 3rd Ed. Oxford: Blackwell Scientific Publications.Google Scholar
Weinberg, E. D., 1984. Iron witholding: a defense against infection and neoplasia. Physiological Reviews 64, 65–102.CrossRefGoogle Scholar
Weinberg, E. D., 1990. Cellular iron metabolism in health and disease. Drug Metabolism Reviews 22, 531–79.CrossRefGoogle ScholarPubMed
Whitehead, S., & Peto, T., 1990. Stage-dependent effect of deferoxamine on growth of Plasmodium falciparum in vitro. Blood 76, 1250–5.CrossRefGoogle ScholarPubMed
Wrigglesworth, J. M., & Baum, H., 1980. The biochemical functions of iron. In Iron in biochemistry and medicine II, pp. 29–86, eds Jacobs, A. & Worwood, M. London: Academic Press.Google Scholar
Wrigglesworth, J. M., & 1988. Iron-dependent enzymes in the brain: In Brain iron: neurochemical and behavioural aspects, eds Moussa, B. H., & Youdim, B. H., London: Taylor and Francis.Google Scholar
Yoshino, S., Blake, D. R., & Bacon, P. A., 1984. The effect of deferoxamine on antigen induced inflammation in the rat air pouch. Journal of Pharmacy and Pharmacology 36, 543–5.CrossRefGoogle ScholarPubMed
Zähner, H., Diddeus, H., Keller-Schierlein, W., & Naegli, H. U., 1977. Some experiments with semisynthetic sideromycins. Japanese Journal of Antibiotics 30, 5201–05.Google ScholarPubMed
Zurlo, M. G., De Stefano, P., Borgna-Pignatti, C., Di Palma, A., Piga, A., Melevendi, C., Di Gregorio, F., Burattini, M. G., & Terzoli, S., 1989. Survival and causes of death in thalassaemia major. The Lancet II, 27–30.CrossRefGoogle Scholar
Zweier, J. L., 1985. Iron-mediated formation of an oxidised adriamycin free radical. Biochemica et Biophysica Acta 839, 209–13.CrossRefGoogle ScholarPubMed