Synthetic and Natural Products as Iron Chelators

Current Topics in Medicinal Chemistry

Volumn 11, Issue 5, 2011, Pages 591-607

  Sharpe, Philip C ^a,b   des Richardson, R ^a,b   Kalinowski, Danuta S ^a,b   Bernhardt, Paul V ^a,b  

^a UNIVERSITY OF QUEENSLAND   (Australia)

^b UNIVERSITY OF SYDNEY   (Australia)

Author keywords

Deferasirox; Deferiprone; Deferitrin; Desferrioxamine; Hemochromatosis; Iron; Iron overload; Thalassemia

Indexed keywords

1,4,7 TRIAZACYCLONONANE 1,4,7 TRIYLTRIMETHYLENETRIS(PHENYLPHOSPHINATE); 2 PYRIDINECARBALDEHYDE ISONICOTINOYL DERIVATIVE; CLIOQUINOL; CURCUMIN; DEFERASIROX; DEFERIPRONE; DEFERITRIN; DEFEROXAMINE; DEFERRIFERRITHIOCIN; DEOFIX; EPIGALLOCATECHIN GALLATE; FEROFIX A; GREEN TEA EXTRACT; HEXDENTATE HYDROXYPYRIDINONE CHELATOR; IRC 011; IRON CHELATING AGENT; N',N',N'' TRIS(DIHYDROXYPHOSPHORYLETHYL) 1,4,7 TRIAZACYCLONONANE; NATURAL PRODUCT; NIFEDIPINE; PEGINTERFERON; PENTETIC ACID; PYRIDOXAL ISONICOTINOYLHYDRAZONE; RASAGILINE; RIBAVIRIN; SELEGILINE; SILIBININ; UNCLASSIFIED DRUG;

ARTICLE; BETA THALASSEMIA; BINDING AFFINITY; CRYSTAL STRUCTURE; DRUG ABSORPTION; DRUG ACTIVITY; DRUG APPROVAL; DRUG BINDING; DRUG BIOAVAILABILITY; DRUG COST; DRUG DELIVERY SYSTEM; DRUG EFFICACY; DRUG FORMULATION; DRUG HALF LIFE; DRUG SAFETY; DRUG SYNTHESIS; HEART DISEASE; HEPATITIS C; HUMAN; INFECTION; IRON CHELATION; IRON OVERLOAD; MALARIA; NONHUMAN; PARKINSON DISEASE; STRUCTURE ACTIVITY RELATION; TEA; THALASSEMIA MAJOR;

EID: 84984984338     PISSN: 15680266     EISSN: None     Source Type: Journal    
DOI: 10.2174/156802611794785163     Document Type: Article

References (164)

1. Atanasiu, V.; Manolescu, B.; Stoian, I. Hepcidin-central regulator of iron metabolism. Eur. J. Haematol., 2007, 78, 1-10.
2. Ganz, T. Molecular control of iron transport. J. Am. Soc. Nephrol., 2007, 18, 394-400.
3. Richardson, D. R.; Ponka, P. The molecular mechanisms of the metabolism and transport of iron in normal and neoplastic cells. Biochim. Biophys. Acta, 1997, 1331, 1-40.
4. Evans, R. W.; Rafique, R.; Zarea, A.; Rapisarda, C.; Cammack, R.; Evans, P. J.; Porter, J. B.; Hider, R. C. Nature of non-transferrin-bound iron: studies on iron citrate complexes and thalassemic sera. J. Biol. Inorg. Chem., 2008, 13, 57-74.
5. Jacobs, A. Low molecular weight intracellular iron transport compounds. Blood, 1977, 50, 433-9.
6. Richardson, D. R.; Dickson, L.; Baker, E. Intermediate steps in cellular iron uptake from transferrin. II. A cytoplasmic pool of iron is released from cultured cells via temperature-dependent mechanical wounding. In Vitro Cell Dev. Biol. Anim., 1996, 32, 486-495.
7. Sheftel, A. D.; Zhang, A. S.; Brown, C.; Shirihai, O. S.; Ponka, P. Direct interorganellar transfer of iron from endosome to mitochondrion. Blood, 2007, 110, 125-132.
8. 2+channel blockers reverse iron overload by a new mechanism via divalent metal transporter-1. Nat. Med., 2007, 13, 448-454.
9. Wood, M. J.; Skoien, R.; Powell, L. W. The global burden of iron overload. Hepatol. Int., 2009, [Epub ahead of print]
10. Allen, K. J.; Gurrin, L. C.; Constantine, C. C.; Osborne, N. J.; Delatycki, M. B.; Nicoll, A. J.; McLaren, C. E.; Bahlo, M.; Nisselle, A. E.; Vulpe, C. D.; Anderson, G. J.; Southey, M. C.; Giles, G. G.; English, D. R.; Hopper, J. L.; Olynyk, J. K.; Powell, L. W.; Gertig, D. M. Iron-overload-related disease in HFE hereditary hemochromatosis. N. Engl. J. Med., 2008, 358, 221-230.
11. Barton, J. C.; McDonnell, S. M.; Adams, P. C.; Brissot, P.; Powell, L. W.; Edwards, C. Q.; Cook, J. D.; Kowdley, K. V. Management of hemochromatosis. Hemochromatosis Management Working Group. Ann. Intern. Med., 1998, 129, 932-939.
12. Cohen, A. R.; Glimm, E.; Porter, J. B. Effect of transfusional iron intake on response to chelation therapy in beta-thalassemia major. Blood, 2008, 111, 583-7.
13. Hatunic, M.; Finucane, F. M.; Brennan, A. M.; Norris, S.; Pacini, G.; Nolan, J. J. Effect of iron overload on glucose metabolism in patients with hereditary hemochromatosis. Metabol. Clin. Exp., 2010, 59, 380-384.
14. Dunford, H. B. Oxidations of iron(II)/(III) by hydrogen peroxide: from aquo to enzyme. Coord. Chem. Rev., 2002, 233, 311-318.
15. Henle, E. S.; Han, Z. X.; Tang, N.; Rai, P.; Luo, Y. Z.; Linn, S. Sequence-specific DNA cleavage by Fe2+-mediated fenton reactions has possible biological implications. J. Biol. Chem., 1999, 274, 962-971.
16. Burkitt, M. J. Chemical, biological and medical controversies surrounding the Fenton reaction. Prog. React. Kin. Mech., 2003, 28, 75-103.
17. Bernhardt, P. V. Coordination chemistry and biology of chelators for the treatment of iron overload disorders. Dalton Trans., 2007, (30) 3214-3220.
18. Crisponi, G.; Remelli, M. Iron chelating agents for the treatment of iron overload. Coord. Chem. Rev., 2008, 252, 1225-1240.
19. Prelog, V.; Walser, A. Metabolic products of actinomycetes. XXXVI. Synthesis of Ferrioxamines B and D. Helv. Chim. Acta, 1962, 45, 631-637.
20. Tripod, J.; Keberle, H. Biological tests with deferrioxamine. Helv. Physiol. Pharmacol. Acta, 1962, 20, 291-293.
21. Brunner, H.; Peters, G.; Jaques, R. Action of desferrioxamine methanesulfonate on circulation and kidney function. Helv. Physiol. Pharmacol. Acta, 1963, 21, C3-C6.
22. Keberle, H. The biochemistry of deferrioxamine and its relation to iron metabolism. Ann. N Y Acad. Sci., 1964, 119, 758-68.
23. Bergeron, R. J.; Pegram, J. J. An efficient total synthesis of desferrioxamine B. J. Org. Chem., 1988, 53, 3131-3134.
24. Raymond, K. N.; Carrano, C. J. Coordination chemistry and microbial iron transport. Acc. Chem. Res., 1979, 12, 183-190.
25. Dhungana, S.; White, P. S.; Crumbliss, A. L. Crystal structure of ferrioxamine B: a comparative analysis and implications for molecular recognition. J. Biol. Inorg. Chem., 2001, 6, 810-818.
26. Dhungana, S.; White, P. S.; Crumbliss, A. L. Crystal and molecular structures of ionophore-siderophore host-guest supramolecular assemblies relevant to molecular recognition. J. Am. Chem. Soc., 2003, 125, 14760-14767.
27. Hossain, M. B.; Jalal, M. A. F.; Van der Helm, D. The structure of ferrioxamine D1-ethanol-water (1/2/1). Acta Crystallogr. Sect. C, 1986, C42, 1305-1310.
28. Van der Helm, D.; Poling, M. The crystal structure of ferrioxamine E. J. Am. Chem. Soc., 1976, 98, 82-86
29. Hossain, M. B.; Jalal, M. A. F.; Van Der Helm, D.; Shimizu, K.; Akiyama, M. Crystal structure of retro-isomer of the siderophore ferrioxamine E. J. Chem. Crystallogr., 1998, 28, 53-56.
30. Smith, R. M.; Martell, A. E.; Motekaitis, R. J. NIST critically selected stability constants of metal complexes database. Version 8.0. ed.; Standard Reference Data Program, National Institute of Standards and Technology, U.S. Dept. of Commerce: Gaithersburg, MD 2004; p 1.
31. Spasojevic, I.; Armstrong, S. K.; Brickman, T. J.; Crumbliss, A. L. Electrochemical behavior of the Fe(III) complexes of the cyclic hydroxamate siderophores alcaligin and desferrioxamine E. Inorg. Chem., 1999, 38, 449-454.
32. Mies, K. A.; Wirgau, J. I.; Crumbliss, A. L. Ternary complex formation facilitates a redox mechanism for iron release from a siderophore. BioMetals, 2006, 19, 115-126.
33. Mies, K. A.; Crumbliss, A. L. Evidence That NADH Can Directly Reduce An Iron-Siderophore and Facilitate Iron Release. Abs., 61st Southeast Regional ACS Meeting, San Juan, Puerto Rico, October 21-24 2009, pp. SRM-589.
34. Crumbliss, A. L. personal communication
35. Harrington, J. M.; Crumbliss, A. L. The redox hypothesis in siderophore-mediated iron uptake. BioMetals, 2009, 22, 679-689.
36. Farrugia, L. J. ORTEP-3 for windows-a version of ORTEP-III with a graphical user interface (GUI). J. Appl. Crystallogr., 1997, 30, 565.
37. Allen, F. H. The CSD. Acta Cryst., Sect. B, 2002, B58, 380-388
38. Kontoghiorghes, G. J.; Eracleous, E.; Economides, C.; Kolnagou, A. Advances in iron overload therapies. Prospects for effective use of deferiprone (L1), deferoxamine, the new experimental chelators ICL670, GT56-252, L1NA11 and their combinations. Curr. Med. Chem., 2005, 12, 2663-2681.
39. Angastiniotis, M.; Modell, B. Global epidemiology of hemoglobin disorders. Ann. N Y. Acad. Sci., 1998, 850, 251-69.
40. Vento, S.; Cainelli, F.; Cesario, F. Infections and thalassaemia. Lancet Infect. Dis., 2006, 6, 226-233.
41. Sebulsky, M. T.; Hohnstein, D.; Hunter, M. D.; Heinrichs, D. E. Identification and characterization of a membrane permease involved in iron-hydroxamate transport in Staphylococcus aureus. J. Bacteriol., 2000, 182, 4394-400.
42. Ibrahim, A. S.; Edwards, J. E., Jr.; Fu, Y.; Spellberg, B. Deferiprone iron chelation as a novel therapy for experimental mucormycosis. J. Antimicrob. Chemother., 2006, 58, 1070-1073.
43. Kim, C. M.; Shin, S. H. Effect of iron-chelator deferiprone on the in vitro growth of staphylococci. J Korean Med. Sci., 2009, 24, 289-295.
44. Neupane, G. P.; Kim, D. M. Comparison of the effects of deferasirox, deferiprone, and deferoxamine on the growth and virulence of Vibrio vulnificus. Transfusion, 2009, 49, 1762-1769.
45. Dragsten, P. R.; Hallaway, P. E.; Hanson, G. J.; Berger, A. E.; Bernard, B.; Hedlund, B. E. First human studies with a high-molecular-weight iron chelator. J. Lab. Clin. Med., 2000, 135, 57-65.
46. Toliyat, T.; Jorjani, M.; Khorasanirad, Z. An extended-release formulation of desferrioxamine for subcutaneous administration. Drug Deliv., 2009, 16, 416-421.
47. Kontoghiorghes, G. J.; Pattichis, K.; Neocleous, K.; Kolnagou, A. The design and development of deferiprone (L1) and other iron chelators for clinical use: targeting methods and application prospects. Curr. Med. Chem., 2004, 11, 2161-2183.
48. Dobbin, P. S.; Hider, R. C.; Hall, A. D.; Taylor, P. D.; Sarpong, P.; Porter, J. B.; Xiao, G.; van der Helm, D. Synthesis, physicochemical properties, and biological evaluation of N-substituted 2-alkyl-3-hydroxy-4(1H)-pyridinones: orally active iron chelators with clinical potential. J. Med. Chem., 1993, 36, 2448-2458.
49. Charalambous, J.; Dodd, A.; McPartlin, M.; Matondo, S. O. C.; Pathirana, N. D.; Powell, H. R. Synthesis and X-ray crystal structure of tris(1,2-dimethyl-3-hydroxypyrid-4-onato)iron(III). Polyhedron, 1988, 7, 2235-2237.
50. Clarke, E. T.; Martell, A. E.; Reibenspies, J. Crystal structure of the tris 1,2-dimethyl-3-hydroxy-4-pyridinone (DMHP) complex with the Fe(III) ion. Inorg. Chim. Acta, 1992, 196, 177-183.
51. Lu, Z.-S.; Niu, D.-Z.; Sun, B.-W. Synthesis and crystal structure of tris(N-p-methylphenyl-3-hydroxy-2-ethyl-4-pyridinonato)iron(III). Jiegou Huaxue, 2001, 20, 466-469.
52. Tam, T. F.; Leung-Toung, R.; Wang, Y.; Spino, M.; Lough, A. J. Tris(1-cyclopropyl-6-methyl-2-(N-methylaminocarbonyl)-4-oxo-1,4-dihydropyridin-4-olato)iron(III) dimethylformamide sesquisolvate dihydrate. Acta Cryst., Sect. E, 2005, E61, m2601-2603.
53. Tam, T. F.; Leung-Toung, R.; Wang, Y.; Spino, M.; Williams, G.; Lough, A. J. Tris(2-N-methylaminocarbonyl-3-hydroxy-1,6-dimethyl-1,4-dihydro-4-pyridinonato)iron(III) dimethylformamide disolvate. Acta Cryst., Sect., E, 2005, E61, m2055-2057.
54. Gaboriau, F.; Chantrel-Groussard, K.; Rakba, N.; Loyer, P.; Pasdeloup, N.; Hider, R. C.; Brissot, P.; Lescoat, G. Iron mobilization, cytoprotection, and inhibition of cell proliferation in normal and transformed rat hepatocyte cultures by the hydroxypyridinone CP411, compared to CP20: a biological and physicochemical study. Biochem. Pharmacol., 2004, 67, 1479-1487.
55. Kline, M. A.; Orvig, C. Complexation of iron with the orally active decorporation drug L1 (3-hydroxy-1,2-dimethyl-4-pyridinone). Clin. Chem., 1992, 38, 562-565.
56. Brady, M. C.; Lilley, K. S.; Treffry, A.; Harrison, P. M.; Hider, R. C.; Taylor, P. D. Release of iron from ferritin molecules and their iron-cores by 3-hydroxypyridinone chelators in vitro. J. Inorg. Biochem., 1989, 35, 9-22.
57. Faller, B.; Nick, H. Kinetics and mechanism of iron(III) Removal from citrate by desferrioxamine B and 3-hydroxy-1,2-dimethyl-4-pyridone. J. Am. Chem. Soc., 1994, 116, 3860-3865.
58. Merkofer, M.; Kissner, R.; Hider, R. C.; Koppenol, W. H. Redox properties of the iron complexes of orally active iron chelators CP20, CP502, CP509, and ICL670. Helv. Chim. Acta, 2004, 87, 3021-3034.
59. Devanur, L. D.; Neubert, H.; Hider, R. C. The Fenton activity of iron(III) in the presence of deferiprone. J. Pharm. Sci., 2008, 97, 1454-1467.
60. Neubert, H.; Hider, R. C.; Cowan, D. A. Speciation of Fe(III)-chelate complexes by electrospray ionization ion trap and laser desorption/ionization Fourier transform ion cyclotron resonance mass spectrometry. Rapid Commun. Mass Spectrom., 2002, 16, 1556-1561.
61. al-Refaie, F. N.; Hoffbrand, A. V. Oral iron-chelating therapy: the L1 experience. Bailliere's Clin. Haematol., 1994, 7, 941-963.
62. Cohen, A. R. New advances in iron chelation therapy. Hematology, 2006, 42-47.
63. Kontoghiorghes, G. J. New orally active iron chelators. Lancet 1985, 1, 817.
64. Gyparaki, M.; Porter, J. B.; Huehns, E. R.; Hider, R. C. Evaluation of in vivo of hydroxypyrid-4-one iron chelators intended for the treatment of iron overload by the oral route. Biochem. Soc. Trans., 1986, 14, 1181.
65. Porter, J. B.; Gyparaki, M.; Burke, L. C.; Huehns, E. R.; Sarpong, P.; Saez, V.; Hider, R. C. Iron mobilization from hepatocyte monolayer cultures by chelators: the importance of membrane permeability and the iron-binding constant. Blood, 1988, 72, 1497-1503.
66. Porter, J. B.; Hoyes, K. P.; Abeysinghe, R.; Huehns, E. R.; Hider, R. C. Animal toxicology of iron chelator L1. Lancet, 1989, 2, 156.
67. Kontoghiorghes, G. J.; Aldouri, M. A.; Sheppard, L. N.; Hoffbrand, A. V. 1,2-dimethyl-3-hydroxypyrid-4-one, an orally active chelator for treatment of iron overload. Lancet, 1987, 329, 1294-1295.
68. al-Refaie, F. N.; Wonke, B.; Hoffbrand, A. V.; Wickens, D. G.; Nortey, P.; Kontoghiorghes, G. J. Efficacy and possible adverse effects of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) in thalassemia major. Blood, 1992, 80, 593-599.
69. Olivieri, N. F.; Koren, G.; Hermann, C.; Bentur, Y.; Chung, D.; Klein, J.; St Louis, P.; Freedman, M. H.; McClelland, R. A.; Templeton, D. M. Comparison of oral iron chelator L1 and desferrioxamine in iron-loaded patients. Lancet, 1990, 336, 1275-1279.
70. Olivieri, N. F.; Koren, G.; Matsui, D.; Liu, P. P.; Blendis, L.; Cameron, R.; McClelland, R. A.; Templeton, D. M. Reduction of tissue iron stores and normalization of serum ferritin during treatment with the oral iron chelator L1 in thalassemia intermedia. Blood, 1992, 79, 2741-2748.
71. Berdoukas, V.; Bentley, P.; Frost, H.; Schnebli, H. P. Toxicity of oral iron chelator L1. Lancet, 1993, 341, 1088.
72. Hershko, C. Development of oral iron chelator L1. Lancet, 1993, 341, 1088-1089.
73. Kontoghiorghes, G. J.; Agarwal, M. B.; Tondury, P.; Kersten, M. J.; Jaeger, M.; Vreugdenhil, G.; Vania, A.; Rahman, Y. E. Future of oral iron chelator deferiprone. (L1) ICOC committee. Lancet, 1993, 341, 1479-1480.
74. Kontoghiorghes, G. J. Misinformation about deferiprone (L1). Lancet, 1993, 342, 250.
75. Olivieri, N. Reply to HSC clinical trials controversy continues. Nat. Med., 1999, 5, 3.
76. Roberts, D. J.; Brunskill, S. J.; Doree, C.; Williams, S.; Howard, J.; Hyde, C. J. Oral deferiprone for iron chelation in people with thalassaemia. Cochrane Database Syst. Rev., 2007, CD004839.
77. Origa, R.; Bina, P.; Agus, A.; Crobu, G.; Defraia, E.; Dessi, C.; Leoni, G.; Muroni, P. P.; Galanello, R. Combined therapy with deferiprone and desferrioxamine in thalassemia major. Haematologica, 2005, 90, 1309-1314.
78. Fabio, G.; Minonzio, F.; Delbini, P.; Bianchi, A.; Cappellini, M. D. Reversal of cardiac complications by deferiprone and deferoxamine combination therapy in a patient affected by a severe type of juvenile hemochromatosis (JH). Blood, 2007, 109, 362-364.
79. Berdoukas, V.; Chouliaras, G.; Moraitis, P.; Zannikos, K.; Berdoussi, E.; Ladis, V. The efficacy of iron chelator regimes in reducing cardiac and hepatic iron in patients with thalassaemia major: a clinical observational study. J. Cardiovasc. Magn., Reson., 2009, 11, 20.
80. De Domenico, I.; Ward, D. M.; Kaplan, J. Specific iron chelators determine the route of ferritin degradation. Blood, 2009, 114, 4546-4551.
81. Devanur, L. D.; Evans, R. W.; Evans, P. J.; Hider, R. C. Chelator-facilitated removal of iron from transferrin: relevance to combined chelation therapy. Biochem. J., 2008, 409, 439-447.
82. Tam, T. F.; Leung-Toung, R.; Wang, Y.; Zhao, Y. Preparation of fluorinated derivatives of deferiprone as iron chelators for treating iron-overload diseases including neurodegenerative disorders. 2008-CA558, 2008116301, 20080327, 2008.
83. Grazina, R.; Gano, L.; Sebestík, J.; Amelia Santos, M. New tripodal hydroxypyridinone based chelating agents for Fe(III), Al(III) and Ga(III): Synthesis, physico-chemical properties and bioevaluation. J. Inorg. Biochem., 2009, 103, 262-273.
84. Jurchen, K. M. C.; Raymond, K. N. A Bidentate Terephthalamide ligand, TAMmeg, as an entry into terephthalamide-containing therapeutic iron chelating agents. Inorg. Chem., 2006, 45, 2438-2447.
85. Jurchen, K. M. C.; Raymond, K. N. Terephthalamide-containing analogues of TREN-Me-3,2-HOPO. Inorg. Chem., 2006, 45, 1078-1090.
86. Abergel, R. J.; Raymond, K. N. Synthesis and thermodynamic evaluation of mixed hexadentate linear iron chelators containing hydroxypyridinone and terephthalamide units. Inorg. Chem., 2006, 45, 3622-3631.
87. Abergel, R. J.; Raymond, K. N. Terephthalamide-containing ligands: fast removal of iron from transferrin. J. Biol. Inorg. Chem., 2008, 13, 229-240.
88. Zhou, T.; Kong, X. L.; Liu, Z. D.; Liu, D. Y.; Hider, R. C. Synthesis and iron(III)-chelating properties of novel 3-hydroxypyridin-4-one hexadentate ligand-containing copolymers. Biomacromolecules, 2008, 9, 1372-1380.
89. Novartis Annual Report 2009 http://www.novartis.com/newsroom/corporate_publications/index.shtml
90. Heinz, U.; Hegetschweiler, K.; Acklin, P.; Faller, B.; Lattmann, R.; Schnebli, H. P. 4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid: a novel efficient and selective iron(III) complexing agent. Angew. Chem. Int. Ed., 1999, 38, 2568-2570.
91. II. Eur. J. Inorg. Chem., 2004, 4177-4192.
92. Stucky, S.; Koch, N. J.; Heinz, U.; Hegetschweiler, K. 3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazole based ligands-protonation and metal complex formation. Chem. Papers., 2008, 62, 388-397.
93. Stumpf, J. L. Deferasirox. Am. J. Health Syst. Pharm., 2007, 64, 606-616.
94. Chirnomas, D.; Smith, A. L.; Braunstein, J.; Finkelstein, Y.; Pereira, L.; Bergmann, A. K.; Grant, F. D.; Paley, C.; Shannon, M.; Neufeld, E. J. Deferasirox pharmacokinetics in patients with adequate vs. inadequate response. Blood, 2009, 114, 4009-4013.
95. Cappellini, M. D. Long-term efficacy and safety of deferasirox. Blood Rev., 2008, 22 (Suppl 2), S35-41.
96. Kontoghiorghes, G. J. Deferasirox: uncertain future following renal failure fatalities, agranulocytosis and other toxicities. Expert Opin. Drug Saf., 2007, 6, 235-239.
97. Kontoghiorghes, G. J. Transparency and access to full information for the fatal or serious toxicity risks, low efficacy and high price of deferasirox, could increase the prospect of improved iron chelation therapy worldwide. Hemoglobin, 2008, 32, 608-615.
98. Porter, J. B.; Taher, A. T.; Cappellini, M. D.; Vichinsky, E. P. Ethical issues and risk/benefit assessment of iron chelation therapy: advances with deferiprone/deferoxamine combinations and concerns about the safety, efficacy and costs of deferasirox [Kontoghiorghes GJ, Hemoglobin 2008; 32(1-2):1-15.]. Hemoglobin, 2008, 32, 601-607.
99. Mathur, K. B.; Iyer, R. N.; Dhar, M. L. Potential antimycobacterial agents. XVI. Synthesis of some 2-(2-hydroxyphenyl)-2-thiazoline-4-(N-substituted carboxamides). J. Sci. Ind. Res., Sect. B, 1962, 21B, 34-37.
100. Ganguly, P. K.; Gupta, B. M. Antiviral activity of isoquinolines carbazoles and other miscellaneous synthetic chemicals in mice. Ind. J. Med. Res., 1975, 63, 1418-1425.
101. Naegeli, H. U.; Zaehner, H. Metabolites of microorganisms. Part 193. Ferrithiocin. Helv. Chim. Acta, 1980, 63, 1400-1406.
102. Jung, A.; Vosbeck, K. D. Use of iron(III) chelators of the type desferrioxamine-B and desferriferrithiocin in the treatment of malaria. Eur. Pat. Appl., 1987, 214101.
103. Anderegg, G.; Raeber, M. Metal complex formation of a new siderophore desferrithiocin and of three related ligands. J. Chem. Soc., Chem. Commun., 1990, 1194-1196.
104. Langemann, K.; Heineke, D.; Rupprecht, S.; Raymond, K. N. Coordination chemistry of microbial iron transport. 59. nordesferriferrithiocin; comparative coordination chemistry of a prospective therapeutic iron chelating agent. Inorg. Chem., 1996, 35, 5663-5673.
105. Hahn, F. E.; McMurry, T. J.; Hugi, A.; Raymond, K. N. Coordination chemistry of microbial iron transport. 42. Structural and spectroscopic characterization of diastereomeric chromium(III) and cobalt(III) complexes of desferrithiocin. J. Am. Chem. Soc., 1990, 112, 1854-1860.
106. Maichle, C.; Hiller, W.; Straehle, J.; Schechinger, T.; Weser, U. Structural chirality of [bis(desferrithiocin)]copper(II). Acta Crystallogr. Sect. C, 1990, C46, 747-750.
107. Pang, K.; Guo, D.; Duan, C.; Mo, H.; Meng, Q. Generation of an equilibrating collection of crystalline solids from a dynamic combinational library. Inorg. Chem., 2003, 42, 5453-5455.
108. Rice-Evans, C.; Baysal, E.; Peter, H. Effects of desferrithiocin on erythrocytes under extracellular oxidant stress. Biochem. Soc. Trans., 1987, 15, 851-852.
109. Baker, E.; Wong, A.; Peter, H.; Jacobs, A. Desferrithiocin is an effective iron chelator in vivo and in vitro but ferrithiocin is toxic. Br. J. Haematol., 1992, 81, 424-431.
110. Galanello, R.; Forni, G.; Jones, A.; Kelly, A.; Willemsen, A.; He, X.; Johnston, A.; Fuller, D.; Donovan, J.; Piga, A. A Dose escalation study of the pharmacokinetics, safety & efficacy of deferitrin, an oral iron chelator in beta thalassaemia patients. ASH Annu. Meet. Abstr., 2007, 110, 2669-.
111. Bergeron, R. J.; Wiegand, J.; McManis, J. S.; Bharti, N.; Singh, S. Desferrithiocin analogues and nephrotoxicity. J. Med. Chem., 2008, 51, 5993-6004.
112. DeWitte, J. J.; Cox, C. D.; Rasmussen, G. T.; Britigan, B. E. Assessment of structural features of the pseudomonas siderophore pyochelin required for its ability to promote oxidant-mediated endothelial cell injury. Arch. Biochem. Biophys., 2001, 393, 236-44.
113. Laden, K.; Zaklad, H.; Simhon, E. D.; Klein, J. Y.; Cyjon, R. L.; Winchell, H. S. N,N',N-tris(dihydroxyphosphorylmethyl)-1,4,7-triazacyclononane (Deofix) -a high-affinity, high-specificity chelator for first transition series metal cations with significant deodorant, antimicrobial, and antioxidant activity. J. Cosmet. Sci., 2003, 54, 251-261.
114. Antipin, M. Y.; Baranov, A. P.; Kabachnik, M. I.; Medved, T. Y.; Polikarpov, Y. M.; Struchkov, Y. M.; Shcherbakov, B. K. Structure of a N,N',N-tris(dihydroxyphosphorylmethyl)-1,4,7-triazacyclono-nane complex with an encapsulated iron ion. Dokl. Akad. Nauk SSSR, 1986, 287, 130-134.
115. Winchell, H. S.; Klein, J. Y.; Cyjon, R. L.; Simhon, E. D. Polyamino paramagnetic chelates which contain both phosphonate and non-phosphonate moieties for MRI. 94-US8459, 9505118, 19940728, 1995.
116. Cole, E.; Copley, R. C. B.; Howard, J. A. K.; Parker, D.; Ferguson, G.; Gallagher, J. F.; Kaitner, B.; Harrison, A.; Royle, L. 1,4,7-Triazacyclononane-1,4,7-triyltrimethylenetris-(Phenylphosphinate) enforces octahedral geometry-crystal and solution structures of its metal-complexes and comparative biodistribution studies of radiolabeled indium and gallium complexes. J. Chem. Soc. Dalton Trans., 1994, 1619-1629.
117. Kalinowski, D. S.; Richardson, D. R. The evolution of iron chelators for the treatment of iron overload disease and cancer. Pharmacol. Rev., 2005, 57, 547-583.
118. Vitolo, L. M. W.; Hefter, G. T.; Clare, B. W.; Webb, J. Iron chelators of the pyridoxal isonicotinoyl hydrazone class. Part II. Formation constants with iron(III) and iron(II). Inorg. Chim. Acta, 1990, 170, 171-176.
119. Avramovici-Grisaru, S.; Sarel, S.; Cohen, S.; Bauminger, R. E. The synthesis, crystal and molecular structure and oxidation state of iron complex from pyridoxal isonicotinoyl hydrazone and ferrous sulfate. Israel J. Chem., 1985, 25, 288-292.
120. Richardson, D. R.; Hefter, G. T.; May, P. M.; Webb, J.; Baker, E. Iron chelators of the pyridoxal isonicotinoyl hydrazone class. III. Formation constants with calcium(II), magnesium(II) and zinc(II). Biol. Met., 1989, 2, 161-167.
121. 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., 1979, 97, 317-321.
122. Richardson, D. R.; Tran, E. H.; Ponka, P. The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents. Blood, 1995, 86, 4295-4306.
123. Brittenham, G. M. Pyridoxal isonicotinoyl hydrazone: an effective iron-chelator after oral administration. Semin. Hematol., 1990, 27, 112-116.
124. Hoy, T.; Humphrys, J.; Jacobs, A.; Williams, A.; Ponka, P. Effective iron chelation following oral administration of an isoniazid-pyridoxal hydrazone. Br. J. Haematol., 1979, 43, 443-449.
125. Bernhardt, P. V.; Chin, P.; Sharpe, P. C.; Richardson, D. R. Hydrazone chelators for the treatment of iron overload disorders: iron coordination chemistry and biological activity. Dalton Trans., 2007, 3232-3244.
126. Armstrong, C. M.; Bernhardt, P. V.; Chin, P.; Richardson, D. R. Structural variations and formation constants of first-row transition metal complexes of biologically active aroylhydrazones. Eur. J. Inorg. Chem., 2003, 1145-1156.
127. Becker, E.; Richardson, D. R. Development of novel aroylhydrazone ligands for iron chelation therapy: 2-Pyridylcarboxaldehyde isonicotinoyl hydrazone analogs. J. Lab. Clin. Med., 1999, 134, 510-521.
128. Wong, C. S. M.; Kwok, J. C.; Richardson, D. R. PCTH: a novel orally active chelator of the aroylhydrazone class that induces iron excretion from mice. Biochim. Biophys. Acta, 2004, 1739, 70-80.
129. Kontoghiorghes, G. J. Iron mobilization from transferrin and non-transferrin-bound-iron by deferiprone. Implications in the treatment of thalassemia, anemia of chronic disease, cancer and other conditions. Hemoglobin, 2006, 30, 183-200.
130. Bernhardt, P. V.; Chin, P.; Richardson, D. R. Unprecedented oxidation of a biologically active aroylhydrazone chelator catalysed by iron(III): serendipitous identification of diacylhydrazine ligands with high iron chelation efficacy. J. Biol. Inorg. Chem., 2001, 6, 801-809.
131. Bernhardt, P. V.; Chin, P.; Sharpe, P. C.; Wang, J.-Y. C.; Richardson, D. R. Novel diaroylhydrazine ligands as iron chelators: coordination chemistry and biological activity. J. Biol. Inorg. Chem., 2005, 10, 761-777.
132. Bernhardt, P. V.; Chin, P.; Richardson, D. R. Iron catalysed assembly of an asymmetric mixed-ligand triple helicate. Dalton Trans., 2004, 3342-3346.
133. Kalinowski, D. S.; Sharpe, P. C.; Bernhardt, P. V.; Richardson, D. R. Structure-activity relationships of novel iron chelators for the treatment of iron overload disease: the methyl pyrazinylketone isonicotinoyl hydrazone series. J. Med. Chem., 2008, 51, 331-344.
134. Milward, E. A.; Baines, S. K.; Knuiman, M. W.; Bartholomew, H. C.; Divitini, M. L.; Ravine, D. G.; Bruce, D. G.; Olynyk, J. K. Noncitrus fruits as novel dietary environmental modifiers of iron stores in people with or without HFE gene mutations. Mayo Clin. Proc., 2008, 83, 543-549.
135. Hatcher, H.; Planalp, R.; Cho, J.; Torti, F. M.; Torti, S. V. Curcumin: from ancient medicine to current clinical trials. Cell Mol. Life. Sci., 2008, 65, 1631-1652.
136. Tomren, M. A.; Masson, M.; Loftsson, T.; Tonnesen, H. H. Studies on curcumin and curcuminoids XXXI. Symmetric and asymmetric curcuminoids: stability, activity and complexation with cyclodextrin. Int. J. Pharm., 2007, 338, 27-34.
137. Tonnesen, H. H. Solubility and stability of curcumin in solutions containing alginate and other viscosity modifying macromolecules. Studies of curcumin and curcuminoids. XXX. Pharmazie, 2006, 61, 696-700.
138. Borsari, M.; Ferrari, E.; Grandi, R.; Saladini, M. Curcuminoids as potential new iron-chelating agents: spectroscopic, polarographic and potentiometric study on their Fe(III) complexing ability. Inorg. Chim. Acta, 2002, 328, 61-68.
139. Bernabé-Pineda, M.; Ramírez-Silva, M. T.; Romero-Romo, M. A.; González-Vergara, E.; Rojas-Hernández, A. Spectrophotometric and electrochemical determination of the formation constants of the complexes Curcumin-Fe(III)-water and Curcumin-Fe(II)-water. Spectrochim. Acta Part A: Mol. Biomol. Spectr., 2004, 60, 1105-1113.
140. Jiao, Y.; Wilkinson, J. T.; Christine Pietsch, E.; Buss, J. L.; Wang, W.; Planalp, R.; Torti, F. M.; Torti, S. V. Iron chelation in the biological activity of curcumin. Free Radic. Biol. Med., 2006, 40, 1152-1160.
141. Wang, Y. J.; Pan, M. H.; Cheng, A. L.; Lin, L. I.; Ho, Y. S.; Hsieh, C. Y.; Lin, J. K. Stability of curcumin in buffer solutions and characterization of its degradation products. J. Pharm. Biomed. Anal., 1997, 15, 1867-1876.
142. Blasius, R.; Duvoix, A.; Morceau, F.; Schnekenburger, M.; Delhalle, S.; Henry, E.; Dicato, M.; Diederich, M. Curcumin stability and its effect on glutathione S-transferase P1-1 mRNA expression in K562 cells. Ann. N. Y. Acad. Sci., 2004, 1030, 442-448.
143. Leung, M. H.; Kee, T. W. Effective stabilization of curcumin by association to plasma proteins: human serum albumin and fibrinogen. Langmuir, 2009, 25, 5773-5777.
144. Hsu, C. H.; Chuang, S. E.; Hergenhahn, M.; Kuo, M. L.; Lin, J. K.; Hsieh, C. Y.; Cheng, A. L. Pre-clinical and early-phase clinical studies of curcumin as chemopreventive agent for endemic cancers in Taiwan. Gan To Kagaku Ryoho, 2002, 29 (Suppl 1), 194-200.
145. Jiao, Y.; Wilkinson, J. t.; Di, X.; Wang, W.; Hatcher, H.; Kock, N. D.; D'Agostino, R., Jr.; Knovich, M. A.; Torti, F. M.; Torti, S. V. Curcumin, a cancer chemopreventive and chemotherapeutic agent, is a biologically active iron chelator. Blood, 2009, 113, 462-469.
146. Benassi, R.; Ferrari, E.; Grandi, R.; Lazzari, S.; Saladini, M. Synthesis and characterization of new beta-diketo derivatives with iron chelating ability. J. Inorg. Biochem., 2007, 101, 203-213.
147. Lee, D. Y.; Liu, Y. Molecular structure and stereochemistry of silybin A, silybin B, isosilybin A, and isosilybin B, Isolated from Silybum marianum (milk thistle). J. Nat. Prod., 2003, 66, 1171-1174.
148. Borsari, M.; Gabbi, C.; Ghelfi, F.; Grandi, R.; Saladini, M.; Severi, S.; Borella, F. Silybin, a new iron-chelating agent. J. Inorg. Biochem., 2001, 85, 123-129.
149. Gharagozloo, M.; Khoshdel, Z.; Amirghofran, Z. The effect of an iron (III) chelator, silybin, on the proliferation and cell cycle of Jurkat cells: a comparison with desferrioxamine. Eur. J. Pharmacol., 2008, 589, 1-7
150. Morazzoni, P.; Magistretti, M. J.; Giachetti, C.; Zanolo, G. Comparative bioavailability of Silipide, a new flavanolignan complex, in rats. Eur. J. Drug Metab. Pharmacokinet., 1992, 17, 39-44.
151. Comoglio, A.; Tomasi, A.; Malandrino, S.; Poli, G.; Albano, E. Scavenging effect of silipide, a new silybin-phospholipid complex, on ethanol-derived free radicals. Biochem. Pharmacol., 1995, 50, 1313-1316.
152. Bares, J. M.; Berger, J.; Nelson, J. E.; Messner, D. J.; Schildt, S.; Standish, L. J.; Kowdley, K. V. Silybin treatment is associated with reduction in serum ferritin in patients with chronic hepatitis C. J. Clin. Gastroenterol., 2008, 42, 937-944.
153. Ferenci, P.; Scherzer, T. M.; Kerschner, H.; Rutter, K.; Beinhardt, S.; Hofer, H.; Schoniger-Hekele, M.; Holzmann, H.; Steindl-Munda, P. Silibinin is a potent antiviral agent in patients with chronic hepatitis C not responding to pegylated interferon/ribavirin therapy. Gastroenterology, 2008, 135, 1561-1567.
154. Whittington, C. Exacerbation of hemochromatosis by ingestion of milk thistle. Can. Fam. Physician 2007, 53, 1671-1673.
155. Chen, Y.; Xie, S.; Chen, S.; Zeng, S. Glucuronidation of flavonoids by recombinant UGT1A3 and UGT1A9. Biochem. Pharmacol., 2008, 76, 416-425.
156. Kuriyama, S.; Hozawa, A.; Ohmori, K.; Shimazu, T.; Matsui, T.; Ebihara, S.; Awata, S.; Nagatomi, R.; Arai, H.; Tsuji, I. Green tea consumption and cognitive function: a cross-sectional study from the Tsurugaya Project 1. Am. J. Clin. Nutr., 2006, 83, 355-361.
157. Ryan, P.; Hynes, M. J. The kinetics and mechanisms of the complex formation and antioxidant behaviour of the polyphenols EGCg and ECG with iron(III). J. Inorg. Biochem. 2007, 101, 585-593.
158. Suh, K. S.; Chon, S.; Oh, S.; Kim, S. W.; Kim, J. W.; Kim, Y. S.; Woo, J. T. Prooxidative effects of green tea polyphenol (-)-epigallocatethin-3-gallate on the HIT-T15 pancreatic beta cell line. Cell Biol. Toxicol. 2010, 26, 189-99.
159. Thephinlap, C.; Ounjaijean, S.; Khansuwan, U.; Fucharoen, S.; Porter, J. B.; Srichairatanakool, S. Epigallocatechin-3-gallate and epicatechin-3-gallate from green tea decrease plasma non-transferrin bound iron and erythrocyte oxidative stress. Med. Chem. 2007, 3, 289-296.
160. Ounjaijean, S.; Thephinlap, C.; Khansuwan, U.; Phisalapong, C.; Fucharoen, S.; Porter, J. B.; Srichairatanakool, S. Effect of green tea on iron status and oxidative stress in iron-loaded rats. Med. Chem. 2008, 4, 365-70.
161. Kell, D. B. Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases. BMC Med. Genomics 2009, 2, 2.
162. Pietrangelo, A. Iron chelation beyond transfusion iron overload. Am. J. Hematol. 2007, 82, 1142-1146
163. Mandel, S. A.; Amit, T.; Kalfon, L.; Reznichenko, L.; Weinreb, O.; Youdim, M. B. Cell signaling pathways and iron chelation in the neurorestorative activity of green tea polyphenols: special reference to epigallocatechin gallate (EGCG). J. Alzheimer's Dis., 2008, 15, 211-222.
164. Mair, S. M.; Weiss, G. New pharmacological concepts for the treatment of iron overload disorders. Curr. Med. Chem., 2009, 16, 576-590.