Pyridoxal isonicotinoyl hydrazone and its analogues

Advances in Experimental Medicine and Biology

Volumn 509, Issue , 2003, Pages 205-229

  Buss, Joan L ^a   Hermes Lima, Marcelo ^b   Ponka, Prem ^a  

^a MCGILL UNIVERSITY   (Canada)

^b UNIVERSITY OF BRASILIA   (Brazil)

Author keywords

[No Author keywords available]

Indexed keywords

2 HYDROXY 1 NAPHTHALOYL BENZOYLHYDRAZONE; 2 HYDROXY 1 NAPHTHALOYL ISONICOTINOYLHYDRAZONE; HYDRAZONE DERIVATIVE; IRON; IRON COMPLEX; PYRIDOXAL BENZOYLHYDRAZONE; PYRIDOXAL ISONICOTINOYLHYDRAZONE; SALICYLALDEHYDE BENZOYLHYDRAZONE; SALICYLOYL ISONICOTINOYLHYDRAZONE; UNCLASSIFIED DRUG; ANTIOXIDANT; DRUG DERIVATIVE; IRON CHELATING AGENT; ISONIAZID; PYRIDOXAL; PYRIDOXAL ISONICOTINOYL HYDRAZONE;

BILIARY EXCRETION; DRUG STRUCTURE; HUMAN; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; IRON CHELATION; IRON KINETICS; IRON OVERLOAD; NONHUMAN; OXIDATIVE STRESS; PRIORITY JOURNAL; RAT; REVIEW; ANIMAL; CHEMICAL STRUCTURE; CHEMISTRY; DRUG SCREENING; METABOLISM;

ANIMALS; ANTIOXIDANTS; DRUG EVALUATION, PRECLINICAL; HUMANS; IRON; IRON CHELATING AGENTS; IRON OVERLOAD; ISONIAZID; MOLECULAR STRUCTURE; PYRIDOXAL;

EID: 0041808760     PISSN: 00652598     EISSN: None     Source Type: Book Series    
DOI: None     Document Type: Review

References (151)

1. Rouault T, Klausner R. Regulation of iron metabolism in eukaryotes. Curr. Top. Cell Regul. 35, 1-19 (1997).
2. Richardson DR, Ponka P. The molecular mechanisms of the metabolism and transport of iron in normal and neoplastic cells. Biochim. Biophys. Acta. 1331, 1-40 (1997).
3. Aisen P, Enns C, Wessling-Resnick M. Chemistry and biology of eukaryotic iron metabolism. Int. J. Biochem. Cell Biol. 33, 940-959 (2001).
4. Hershko C, Link G, Cabantchik I. Pathophysiology of iron overload. Ann. N. Y. Acad. Sci. 850, 191-201 (1998).
5. Porter JB. Practical management of iron overload. Br. J. Haematol. 115, 239-252 (2001).
6. Hershko C, Konijn AM, Link G. Iron chelators for thalassaemia. Br. J. Haematol. 101, 399-406 (1998).
7. Kontoghiorghes GJ, Aldouri MA, Hoffbrand AV, Barr J, Wonke B, Kourouclaris T, Sheppard L. Effective chelation of iron in beta thalassaemia with the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one. Br. Med. J. 295, 1509-1512 (1987).
8. Olivieri NF, Koren G, St Louis P, Freedman MH, McClelland RA, Templeton DM. Studies of the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one in thalassemiapatients. Semin. Hematol. 27, 101-104 (1990).
9. Berdoukas V, Bentley P, Frost H, Schnebli HP. Toxicity of oral iron chelator L1. Lancet. 341, 1088 (1993).
10. al Refaie FN, Wonke B, Hoffbrand AV. Deferiprone-associated myelotoxicity. Eur. J. Haematol. 53, 298-301 (1994).
11. al Refaie FN, Hoffbrand AV. Oral iron-chelating therapy: the L1 experience. Bailliere's Clin. Haematol. 7, 941-963 (1994).
12. Olivieri NF, Brittenham GM. Iron-chelating therapy and the treatment of thalassemia. Blood. 89, 739-761 (1997).
13. Olivieri NF, Brittenham GM, McLaren CE, Templeton DM, Cameron RG, McClelland RA, Burt A.D, Fleming K.A, Long-term safety and effectiveness of iron-chelation therapy with deferiprone for thalassemia major. N. Engl. J. Med. 339, 417-423 (1998).
14. Richardson DR. The controversial role of deferiprone in the treatment of thalassemia. J. Lab. Clin. Med. 137, 324-329 (2001).
15. Pippard MJ, Weatherall DJ. Oral iron chelation therapy for thalassaemia: an uncertain scene. Br. J. Haematol. 111, 2-5 (2000).
16. Ponka P, Borova J, Neuwirt J, Fuchs O. Mobilization of iron from reticulocytes. Identification of pyridoxal isonicotinoyl hydrazone as a new iron chelating agent. FEBS Lett. 97, 317-321 (1979).
17. Ponka P, Neuwirt J, Borova J, Fuchs O. Control of iron delivery to haemoglobin in erythroid cells. Ciba Foundation Symposium 51 (new series). 167-200 (1977).
18. Ponka P, Borova J, Neuwirt J, Fuchs O, Necas E. A study of intracellular iron metabolism using pyridoxal isonicotinoyl hydrazone and other synthetic chelating agents. Biochim. Biophys. Acta. 586, 278-297 (1979).
19. Hoy T, Humphrys J, Jacobs A, Williams A, Ponka P. Effective iron chelation following oral administration of an isoniazid-pyridoxal hydrazone. Br. J. Haematol. 43, 443-449 (1979).
20. Cikrt M, Ponka P, Necas E, Neuwirt J. Biliary iron excretion in rats following pyridoxal isonicotinoyl hydrazone. Br. J. Haematol. 45, 275-283 (1980).
21. Hershko C, Avramovici-Grisaru S, Link G, Gelfand L, Sarel S. Mechanism of in vivo iron chelation by pyridoxal isonicotinoyl hydrazone and other imino derivatives of pyridoxal. J. Lab. Clin. Med. 98, 99-108 (1981).
22. Pippard MJ, Johnson DK, Finch CA. A rapid assay for evaluation of iron-chelating agents in rats. Blood. 58, 685-692 (1981).
23. Johnson DK, Pippard MJ, Murphy TB, Rose NJ. An in vivo evaluation of iron-chelating drugs derived from pyridoxal and its analogs. J. Pharm. Exp. Ther. 221, 399-403 (1982).
24. Williams A, Hoy T, Pugh A, Jacobs A. Pyridoxal complexes as potential chelating agents for oral therapy in transfusional iron overload. J. Pharm. Pharmacol. 34, 730-732 (1982).
25. Avramovici-Grisaru S, Sarel S, Link G, Hershko C. Syntheses of iron bis(pyridoxal isonicotinoylhydrazone)s and the in vivo iron-removal properties of some pyridoxal derivatives. J. Med. Chem. 26, 298-302 (1983).
26. Webb J, Vitolo ML. Pyridoxal isonicotinoyl hydrazone (PIH): a promising new iron chelator. Birth Defects Orig. Art. Ser. 23, 63-70 (1988).
27. Vitolo ML, Clare BW, Hefter GT, Webb J. Chemical studies of pyridoxal isonicotinoyl hydrazone relevant to its clinical evaluation. Birth Defects Orig. Artic. Ser. 23, 71-79 (1988).
28. Richardson DR, Vitolo LW, Baker E, Webb J. Pyridoxal isonicotinoyl hydrazone and analogues. Study of their stability in acidic, neutral, and basic aqueous solutions by ultraviolet-visible spectrophotometry. Biol. Met. 2, 69-76 (1989).
29. Richardson DR, Hefter GT, May PM, Webb J, Baker E. Iron chelators of the pyridoxal isonicotinoyl hydrazone class. III. Formation constants with calcium(II), magnesium(II) andzinc(II). Biol. Met. 2, 161-167 (1989).
30. Sarel S, Cohen S, Avramovici-Grisaru S. Iron chelators of the class of pyridoxal acylhydrazone - part 5 - crystal structure and patterns of hydrogen bonding in pyridoxal isonicotinoyl hydrazone (PIH). Heterocycles. 47, 1033-1042 (1998).
31. Souron JP, Quarton M, Robert F, Lyubchova A, Cosse-Barbi A, Doucet JP. Pyridoxal isonicotinoyl hydrazone (PIH). a synthetic ion-chelating agent. Acta. Cryst. Sect. C. 51, 2179-2182 (1995).
32. Colonna P, Cosse-Barbi A, Massat A, Doucet JP. IR studies of iron complexes with pyridoxal isonicotinoyl hydrazone and 3 other similar chelating agents. Spectroscopy Lett. 26, 1065-1072 (1993).
33. Morgan EH. Chelator-mediated iron efflux from reticulocytes. Biochim. Biophys. Acta. 733, 39-50 (1983).
34. 59Fe. Biochim Biophys. Acta. 757, 306-315 (1983).
35. Ponka P, Grady RW, Wilczynska A, Schulman HM. The effect of various chelating agents on the mobilization of iron from reticulocytes in the presence and absence of pyridoxal isonicotinoyl hydrazone. Biochim. Biophys. Acta. 802, 477-489 (1984).
36. Baker E, Vitolo ML, Webb J. Iron chelation by pyridoxal isonicotinoyl hydrazone and analogues in hepatocytes in culture. Biochem. Pharmacol. 34, 3011-3017 (1985).
37. Crowe A, Morgan EH. Effects of chelators on iron uptake and release by the brain in the rat. Neurochem. Res. 19, 71-76 (1994).
38. Hallmann R, Savigni DL, Morgan EH, Baker E. Characterization of iron uptake from transferrin by murine endothelial cells. Endothelium. 7, 135-147 (2000).
39. Ponka P, Richardson D, Baker E, Schulman HM, Edward JT. Effect of pyridoxal isonicotinoyl hydrazone and other hydrazones on iron release from macrophages, reticulocytes and hepatocytes. Biochim. Biophys. Acta. 967, 122-129 (1988).
40. Baker E, Richardson D, Gross S, Ponka P. Evaluation of the iron chelation potential of hydrazones of pyridoxal, salicylaldehyde and 2-hydroxy-1-naphthylaldehyde using the hepatocyte in culture. Hepatology. 15, 492-501 (1992).
41. Blaha K, Cikrt M, Nerudova J, Fornuskova H, Ponka P. Biliary iron excretion in rats following treatment with analogs of pyridoxal isonicotinoyl hydrazone. Blood. 91, 4368-4372 (1998).
42. Richardson DR, Ponka P. Pyridoxal isonicotinoyl hydrazone and its analogs: potential orally effective iron-chelating agents for the treatment of iron overload disease. J. Lab. Clin. Med. 131, 306-315 (1998).
43. Richardson DR, Mouralian C, Ponka P, Becker E. Development of potential iron chelators for the treatment of Friedreich's ataxia: ligands that mobilize mitochondrial iron. Biochim. Biophys. Acta. 1536, 133-140 (2001).
44. Hermes-Lima M, Wang EM, Schulman HM, Storey KB, Ponka P. Deoxyribose degradation catalyzed by Fe(III)-EDTA: kinetic aspects and potential usefulness for submicromolar iron measurements. Mol. Cell. Biochem. 137, 65-73 (1994).
45. Bhattacharya M, Ponka P, Hardy P, Hanna N, Varma DR, Lachapelle P, Chemtob S, Prevention of postasphyxia electroretinal dysfunction with a pyridoxal hydrazone. Free Rad. Biol. Med. 22, 11-16 (1997).
46. Hermes-Lima M, Nagy E, Ponka P, Schulman HM. The iron chelator pyridoxal isonicotinoyl hydrazone (PIH) protects plasmid pUC-18 DNA against *OH-mediated strand breaks. Free Rad. Biol. Med. 25, 875-880 (1998).
47. Hermes-Lima M, Santos NC, Yan J, Andrews M, Schulman HM, Ponka P. EPR spin trapping and 2-deoxyribose degradation studies of the effect of pyridoxal isonicotinoyl hydrazone (PIH) on *OH formation by the Fenton reaction. Biochim. Biophys. Acta. 1426, 475-482 (1999).
48. Hermes-Lima M, Ponka P, Schulman HM. The iron chelator pyridoxal isonicotinoyl hydrazone (PIH) and its analogues prevent damage to 2-deoxyribose mediated by ferric iron plus ascorbate. Biochim. Biophys. Acta. 1523, 154-160 (2000).
49. Horackova M, Ponka P, Byczko Z. The antioxidant effects of a novel iron chelator salicylaldehyde isonicotinoyl hydrazone in the prevention of H(2)O(2) injury in adult cardiomyocytes. Cardiovasc. Res. 47, 529-536 (2000).
50. Tsafack A, Loyevsky M, Ponka P, Cabantchik ZI. Mode of action of iron (III) chelators as antimalarials. IV. Potentiation of desferal action by benzoyl and isonicotinoyl hydrazone derivatives. J. Lab. Clin. Med. 127, 574-582 (1996).
51. Golenser J, Domb A, Teomim D, Tsafack A, Nisim O, Eling W, Cabantchik ZI, The treatment of animal models of malaria with iron chelators by use of a novel polymeric device for slow drug release. J. Pharm. Exp. Ther. 281, 1127-1135 (1997).
52. Richardson DR, Tran EH, Ponka P. The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents. Blood. 86, 4295-4306 (1995).
53. Ponka P, Schulman HM, Wilczynska A. Ferric pyridoxal isonicotinoyl hydrazone can provide iron for heme synthesis in reticulocytes. Biochim. Biophys. Acta. 718, 151-156 (1982).
54. Ponka P, Schulman HM. Regulation of heme synthesis in erythroid cells: hemin inhibits transferrin iron utilization but not protoporphyrin synthesis. Blood. 65, 850-857 (1985).
55. Ponka P, Schulman HM. Acquisition of iron from transferrin regulates reticulocyte heme synthesis. J. Biol. Chem. 260, 14717-14721 (1985).
56. Laskey JD, Ponka P, Schulman HM. Control of heme synthesis during Friend cell differentiation: role of iron and transferrin. J. Cell. Physiol. 129, 185-192 (1986).
57. Landschulz W, Thesleff I, Ekblom P. A lipophilic iron chelator can replace transferrin as a stimulator of cell proliferation and differentiation. J. Cell. Biol. 98, 596-601 (1984).
58. Thesleff I, Partanen AM, Landschulz W, Trowbridge IS, Ekblom P. The role of transferrin receptors and iron delivery in mouse embryonic morphogenesis. Differentiation. 30 , 152-158 (1985).
59. Ekblom P, Landschulz W, Andersson LC. A lipophilic iron chelator induces an enhanced proliferation of human erythroleukaemia (HEL) cells. Scand. J. Haematol. 36, 258-262 (1986).
60. Landschulz W, Ekblom P. Iron delivery during proliferation and differentiation of kidney tubules. J. Biol. Chem. 260, 15580-15584 (1985).
61. Forsbeck K, Bjelkenkrantz K, Nilsson K. Role of iron in the proliferation of the established human tumor cell lines U-937 and K-562: effects of suramin and a lipophilic iron chelator (PIH). Scand. J. Haematol. 37, 429-437 (1986).
62. Laskey J, Webb I, Schulman HM, Ponka P. Evidence that transferrin supports cell proliferation by supplying iron for DNA synthesis. Exp. Cell Res. 176, 87-95 (1988).
63. Partanen AM, Thesleff I. Transferrin and tooth morphogenesis: retention of transferrin by mouse embryonic teeth in organ culture. Differentiation. 34, 25-31 (1987).
64. Tsao MS, Sanders GH, Grisham JW. Regulation of growth of cultured hepatic epithelial cells by transferrin. Exp. Cell Res. 171, 52-62. 1987.
65. Brock JH, Stevenson J. Replacement of transferrin in serum-free cultures of mitogen-stimulated mouse lymphocytes by a lipophilic iron chelator. Immunol. Lett. 15, 23-25. 1986.
66. Djeha A, Brock JH. Effect of transferrin, lactoferrin and chelated iron on human T-lymphocytes. Br. J. Haematol. 80, 235-241 (1992).
67. Avramovici-Grisaru S, Sarel S, Cohen S, Bauminger RE. The synthesis, crystal and molecular structure, and oxidation state of iron complex from pyridoxal isonicotinoyl hydrazone and ferrous sulphate. Israel. J. Chem. 25, 288-292 (1985).
68. Murphy TB, Johnson DK, Rose NJ, Aruffo A, Schomaker V. Structural studies of iron(III) complexes of the new iron-binding drug, pyridoxal isonicotinoyl hydrazone. Inorg. Chim. Acta 66, L67-L68. (1982).
69. Becker E, Richardson DR. Development of novel aroylhydrazone ligands for iron chelation therapy: 2-pyridylcarboxaldehyde isonicotinoyl hydrazone analogs. J. Lab. Clin. Med. 134, 510-521 (1999).
70. Richardson DR, Becker E, Bernhardt PV. The biologically active iron chelators 2-pyridylcarboxaldehyde isonicotinoylhydrazone, 2- pyridylcarboxaldehyde benzoylhydrazone monohydrate and 2-furaldehyde isonicotinoylhydrazone. Acta. Cryst. Sect. C. 55, 2102-2105 (1999).
71. Vitolo ML, Hefter GT, Clare BW, Webb J. Iron chelators of the pyridoxal isonicotinoyl hydrazone class Part II. Formation constants with iron(III) and iron(II). Inorg. Chim. Acta. 170, 171-176 (1990).
72. Zak O, Leibman A, Aisen P. Metal-binding properties of a single-sited transferrin fragment. Biochim. Biophys. Acta. 742, 490-495 (1983).
73. Richardson DR, Vitolo ML, Hefter GT, May PM, Clare BW, Webb J. Iron chelators of the pyridoxal isonicotinoyl hydrazone class Part I. Ionization characteristics of the ligands and their relevance to biological properties. Inorg. Chim. Acta 170, 165-170 (1990).
74. Schmidt RF, Thews J. Human Physiology (Springer-Verlag, New York, 1983).
75. Travis S, Menzies IS. Intestinal permeability: functional assessment and significance. Clin. Sci. 82, 471-480 (1992).
76. 51Cr-labelled EDTA, L-rhamnose and polyethyleneglycol 400 as probe markers for assessment in vivo of human intestinal permeability. Clin. Sci. 71, 71-80 (1986).
77. Sah PPT. Nicotinyl and isonicotinyl hydrazones of pyridoxal. J. Am. Chem. Soc. 76, 300 (1954).
78. Brittenham GM. Pyridoxal isonicotinoyl hydrazone: an effective iron-chelator after oral administration. Semin. Hematol. 27, 112-116 (1990).
79. 2+. A spectrophotometric study. J. Chim. Phys. 94, 1195-1207. (1997).
80. Singh G, Shastry PSSJ, Lonibala RK, Rao TR. Coordination behaviour of pyridoxalisonicotinoyl hydrazone towards some 3d-metal ions. Synth. React. Inorg. Met. -Org. Chem. 22:1041-1059 (1992).
81. Edward JT, Ponka P, Richardson DR. Partition coefficients of the iron(III) complexes of pyridoxal isonicotinoyl hydrazone and its analogs and the correlation to iron chelation efficacy. Biometals. 8, 209-217 (1995).
82. Edward JT, Chubb FL, Sangster J. Iron chelators of the pyridoxal isonicotinoyl hydrazone class. Relationship of the lipophilicity of the apochelator to its ability to mobilize iron from reticulocytes in vitro: reappraisal of reported partition coefficients. Can. J. Physiol. Pharmacol. 75, 1362-1368 (1997).
83. Lea A, Hansch C, Elkins D. Partition coefficients and their uses. Chem. Rev. 71, 525-555 (1971).
84. Hider RC. Potential protection from toxicity by oral iron chelators. Toxicol. Lett. 83, 961-967 (1995).
85. Pappenheimer JR, Karnovsky ML, Maggio JE. Absorption and excretion of undegradable peptides: role of lipid solubility and net charge. J. Pharm. Exp. Ther. 280, 292-300 (1997).
86. Ponka P, Wilczynska A, Schulman HM. Iron utilization in rabbit reticulocytes. A study using succinylacetone as an inhibitor of heme synthesis. Biochim. Biophys. Acta. 720, 96-105 (1982).
87. Borova J, Ponka P, Neuwirt J. Study of intracellular iron distribution in rabbit reticulocytes with normal and inhibited heme synthesis. Biochim. Biophys. Acta. 320, 143-156 (1973).
88. Ponka P, Neuwirt J. The use of reticulocytes with high non-haem iron pool for studies of regulation of haem synthesis. Br. J. Haematol. 19, 593-604 (1970).
89. Richardson DR. Mobilization of iron from neoplastic cells by some iron chelators is an energy-dependent process. Biochim. Biophys. Acta. 1320, 45-57 (1997).
90. Harris WR, Carrano CJ, Raymond KN. Co-ordination chemistry of microbial iron transport compounds: Isolation, characterization, and formation constants of ferric aerobactin. J. Am. Chem. Soc. 101, 2722-2727 (1979).
91. Morgan EH. A study of iron transfer from rabbit transferrin to reticulocytes using synthetic chelating agents. Biochim. Biophys. Acta. 244, 103-116 (1971).
92. Martell AE, Smith RM. Critical Stability Constants (New York. 1977).
93. Ponka P, Baker E. The effect of the iron(III) chelator, desferrioxamine, on iron and transferrin uptake by the human malignant melanoma cell. Cancer Res. 54, 685-689 (1994).
94. Bakkeren DL, de Jeu-Jaspars CMH, Kroos MJ, van Eijk HG. Release of iron from endosomes is an early step in the transferrin cycle. Int. J. Biochem. 19, 179-186 (1987).
95. Edward JT, Gauthier M, Chubb FL, Ponka P. Synthesis of new acylhydrazones as iron-chelating compounds. J. Chem. Eng. Data. 33, 538-540 (1988).
96. Richardson DR, Milnes K. The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents II: the mechanism of action of ligands derived from salicylaldehyde benzoyl hydrazone and 2-hydroxy-1-naphthylaldehyde benzoyl hydrazone. Blood. 89, 3025-3038 (1997).
97. Kim S, Ponka P. Effects of interferon-gamma and lipopolysaccharide on macrophage iron metabolism are mediated by nitric oxide-induced degradation of iron regulatory protein 2. J. Biol. Chem. 275, 6220-6226 (2000).
98. Darnell G, Richardson DR. The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents III: The effect of the ligands on molecular targets involved in proliferation. Blood. 94, 781-792 (1999).
99. Eisenstein RS. Iron regulatory proteins and the molecular control of mammalian iron metabolism. Ann. Rev. Nutr. 20, 627-662 (2000).
100. Richardson DR, Ponka P. The iron metabolism of the human neuroblastoma cell: lack of relationship between the efficacy of iron chelation and the inhibition of DNA synthesis. J. Lab. Clin. Med. 124, 660-671 (1994).
101. Ponka P, Richardson DR, Edward JT, Chubb FL. Iron chelators of the pyridoxal isonicotinoyl hydrazone class. Relationship of the lipophilicity of the apochelator to its ability to mobilise iron from reticulocytes in vitro. Can. J. Physiol. Pharmacol. 72, 659-666 (1994).
102. Baker E, Page M, Torrance J, Grady R. Effect of desferrioxamine, rhodotorulic acid and cholylhydroxamic acid on transferrin and iron exchange with hepatocytes in culture. Clin. Physiol. Biochem. 3, 277-288 (1985).
103. Hershko C. Determinants of fecal and urinary iron excretion in desferrioxamine-treated rats. Blood. 51, 415-423 (1978).
104. Lipschitz DA, Simon MO, Lynch SR, Dugard J, Bothwell TH, Charlton RW. Some factors affecting the release of iron from reticuloendothelial cells. Br. J. Haematol. 21, 289-303 (1971).
105. Sharma BK, Tavill AS, Louis LN, Wiesen E, Vames AW. Enteral pyridoxal isonicotinoyl hydrazone (PIH) is an effective chelator in experimental iron overload by promotion of biliary iron excretion. Hepatology. 10, 573 (1989).
106. Sharma BK, Tavill AS, Louis LN, Vames AW. Predominance of biliary iron chelates in iron-loaded rats in vivo during i.v. deferoxamine (DF) or pyridoxal isonicotinoyl hydrazone (PIH). Hepatology. 8, 1240 (1988).
107. Kim BK, Huebers HA, Finch CA. Effectiveness of oral iron chelators assayed in the rat. Am. J. Hematol. 24, 277-284 (1987).
108. Pootrakul P, Yansukon P, Piankijagum A, Muangsub W, Brittenham GM. The interference of pyridoxal isonicotinoyl hydrazone with intestinal iron absorption. Ann. N. Y. Acad. Sci. 124, 582-584 (1990).
109. Summers MR, Jacobs A, Tudway D, Perera P, Ricketts C. Studies in desferrioxamine and ferrioxamine metabolism in normal and iron-loaded subjects. Br. J. Haematol. 42, 547-555 (1979).
110. Djeha A, Brock JH. Uptake and intracellular handling of iron from transferrin and iron chelates by mitogen stimulated mouse lymphocytes. Biochim. Biophys. Acta. 1133, 147-152 (1992).
111. Alcantara O, Obeid L, Hannun Y, Ponka P, Boldt DH. Regulation of protein kinase C (PKC) expression by iron: effect of different iron compounds on PKC-beta and PKC-alpha gene expression and role of the 5′-flanking region of the PKC-beta gene in the response to ferric transferrin. Blood. 84, 3510-3517 (1994).
112. Thelander L, Reichard P. Reduction of ribonucleotides. Ann. Rev. Biochem. 48, 133-158 (1979).
113. Nyholm S, Mann GJ, Johansson AG, Bergeron RJ, Graslund A, Thelander L. Role of ribonucleotide reductase in inhibition of mammalian cell growth by potent iron chelators. J. Biol. Chem. 268, 26200-26205 (1993).
114. Green DA, Antholine WE, Wong SJ, Richardson DR, Chitambar CR. Inhibition of malignant cell growth by 311, a novel iron chelator of the pyridoxal isonicotinoyl hydrazone class: effect on the R2 subunit of ribonucleotide reductase. Clin. Cancer Res. 7, 3574-3579 (2001).
115. Hoffbrand AV, Ganeshaguru K, Hooton JW, Tattersall MH. Effect of iron deficiency and desferrioxamine on DNA synthesis in human cells. Br. J. Haematol. 33, 517-526 (1976).
116. Hoyes KP, Hider RC, Porter JB. Cell cycle synchronization and growth inhibition by 3-hydroxypyridin-4-one iron chelators in leukemia cell lines. Cancer Res. 52, 4591-4599 (1992).
117. Brodie C, Siriwardana G, Lucas J, Schleicher R, Terada N, Szepesi A, Gelfand E, Seligman P. Neuroblastoma sensitivity to growth inhibition by deferrioxamine: evidence for a block in G1 phase of the cell cycle. Cancer Res. 53, 3968-3975 (1993).
118. van Reyk D, Sarel S, Hunt N. Inhibition of in vitro lymphoproliferation by three novel iron chelators of the pyridoxal and salicyl aldehyde hydrazone classes. Biochem. Pharmacol. 60, 581-587 (2000).
119. Bomford A, Isaac J, Roberts S, Edwards A, Young S, Williams R. The effect of desferrioxamine on transferrin receptors, the cell cycle and growth rates of human leukaemic cells. Biochem. J. 236, 243-249 (1986).
120. Renton FJ, Jeitner TM. Cell cycle-dependent inhibition of the proliferation of human neural tumor cell lines by iron chelators. Biochem. Pharmacol. 51, 1553-1561 (1996).
121. Levine AJ. p53, the cellular gatekeeper for growth and division. Cell. 88, 323-331 (1997).
122. Momand J, Zambetti GP, Olson DC, George D, Levine AJ. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell. 69, 1237-1245 (1992).
123. Gao J, Richardson DR. The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents, IV: The mechanisms involved in inhibiting cell-cycle progression. Blood. 98, 842-850 (2001).
124. Wu X, Bayle JH, Olson D, Levine AJ. The p53-mdm-2 autoregulatory feedback loop. Genes Dev. 7, 1126-1132 (1993).
125. Koh LL, Kon OL, Loh KW, Long YC, Ranford JD, Tan AL, Tjan YY. Complexes of salicylaldehyde acylhydrazones: cytotoxicity, QSAR and crystal structure of the sterically hindered t-butyl dimer. J. Inorg. Biochem. 72, 155-162 (1998).
126. Forsbeck K, Nilsson K, Kontoghiorghes GJ. Variation in iron accumulation, transferrin membrane binding and DNA synthesis in the K-562 and U-937 cell lines induced by chelators and their iron complexes. Eur. J. Haematol. 39, 318-325 (1987).
127. Edward JT. Partition coefficients of the iron (III) complexes of pyridoxal isonicotinoyl hydrazone and its analogs and the correlation to iron chelation efficacy. Correction of some reported partition coefficients. Biometals. 11, 203-205 (1998).
128. Richardson DR, Bemhardt PV. Crystal and molecular structure of 2-hydroxy-1-naphthaldehyde isonicotinoyl hydrazone (NIH) and its iron(III) complex: an iron chelator with anti-tumour activity. J. Biol. Inorg. Chem. 4, 266-273 (1999).
129. Seligman PA, Schleicher RB, Siriwardana G, Domenico J, Gelfand EW. Effects of agents that inhibit cellular iron incorporation on bladder cancer cell proliferation. Blood. 82, 1608-1617 (1993).
130. Chitambar CR, Narasimhan J, Guy J, Sem DS, O'Brien WJ. Inhibition of ribonucleotide reductase by gallium in murine leukemic LI210 cells. Cancer Res. 51, 6199-6201 (1991).
131. Seligman PA, Moran PL, Schleicher RB, Crawford ED. Treatment with gallium nitrate: evidence for interference with iron metabolism in vivo. Am. J. Hematol. 41, 232-240 (1992).
132. Chitambar CR, Zivkovic Z. Inhibition of hemoglobin production by transferrin-gallium. Blood. 69, 144-149 (1987).
133. Brittenham GM. Pyridoxal isonicotinoyl hydrazone. Effective iron chelation after oral administration. Ann. N. Y. Acad. Sci. 612, 315-326 (1990).
134. Sookvanichsilp N, Nakornchai S, Weerapradist W. Toxicological study of pyridoxal isonicotinoyl hydrazone: acute and subchronic toxicity. Drug Chem. Toxicol. 14, 395-403 (1991).
135. Mohan M, Kumar A, Kuo YM. Synthesis, characterization and antitumour activity of manganese(II), cobalt(II), nickel(II), copper(II), zinz(II) and platinum(II) complexes of 3-and 5-substituted salicylaldehyde benzoylhydrazones. Inorg. Chim. Acta. 136, 65-74 (1987).
136. Lees-Gayed NJ, Abou-Taleb MA, El-Bitash IA, Iskandei MF. Studies on biologically active acylhydrazones. Part I. Acid-base equilibria and acid hydrolysis of pyridoxal aroylhydrazones and related compounds. J. Chem. Soc. Perkin 2, 213-217 (1992).
137. Schaumburg H, Kaplan J, Windebank A, Vick N, Rasmus S, Pleasure D, Brown MJ. Sensory neuropathy from pyridoxine abuse. A new megavitamin syndrome. N. Engl. J. Med. 309, 445-448 (1983).
138. Scott MD, Ranz A, Kuypers FA, Lubin BH, Meshnick SR. Parasite uptake of desferroxamine: a prerequisite for antimalarial activity. Br. J. Haematol. 75, 598-602 (1990).
139. Gutteridge JM, Halliwell B. Iron toxicity and oxygen radicals. Bailliere's Clin. Haematol. 2, 195-256 (1989).
140. Halliwell B, Gutteridge JM. Oxygen toxicity, oxygen radicals, transition metals and disease. Biochem. J. 219, 1-14 (1984).
141. Halliwell B, Gutteridge JM. Role of free radicals and catalytic metal ions in human disease: an overview. Meth. Enzymol. 186, 1-85 (1990).
142. Reddy BR, Kloner RA, Przyklenk K. Early treatment with deferoxamine limits myocardial ischemic/reperfusion injury. Free Rad. Biol. Med. 7, 45-52 (1989).
143. Healing G, Gower J, Fuller B, Green C. Intracellular iron redistribution. An important determinant of reperfusion damage to rabbit kidneys. Biochem. Pharmacol. 39, 1239-1245 (1990).
144. Biemond P, Swaak AJ, van Eijk HG, Koster JF. Superoxide dependent iron release from ferritin in inflammatory diseases. Free Rad. Biol. Med. 4, 185-198 (1988).
145. Toyokuni S. Iron-induced carcinogenesis: the role of redox regulation. Free Rad. Biol. Med. 20, 553-566 (1996).
146. Gassen M, Youdim MB. The potential role of iron chelators in the treatment of Parkinson's disease and related neurological disorders. Pharmacol. Toxicol. 80, 159-166 (1997).
147. Schulman HM, Hermes-Lima M, Wang EM, Ponka P. In vitro antioxidant properties of the iron chelator pyridoxal isonicotinoyl hydrazone and some of its analogs. Redox Rep. 1, 373-378 (1995).
148. Santos NC, Castilho RF, Meinicke AR, Hermes-Lima M. The iron chelator pyridoxal isonicotinoyl hydrazone inhibits mitochondrial lipid peroxidation induced by Fe(II)-citrate. Eur. J. Pharmacol. 428, 37-44 (2001).
149. Fuchs O. Effects of intracellular chelatable iron and oxidative stress on transcription of classical cellular glutathione peroxidase gene in murine erythroleukemia cells. Neoplasma. 44, 184-191 (1997).
150. Cable H, Lloyd JB. Cellular uptake and release of two contrasting iron chelators. J. Pharm. Pharmacol. 51, 131-134 (1999).
151. Ferrali M, Signorini C, Ciccoli L, Bambagioni S, Rossi V, Pompella A, Comporti M. Protection of erythrocytes against oxidative damage and autologous immunoglobulin G (IgG) binding by iron chelator fluor-benzoilpyridoxal hydrazone. Biochem. Pharmacol. 59, 1365-1373 (2000).