Iron chelators: Development of novel compounds with high and selective anti-tumour activity

Current Drug Delivery

Volumn 7, Issue 3, 2010, Pages 194-207

  Kovacevic, Z ^a   Kalinowski, D S ^a   Lovejoy, D B ^a   Quach, P ^a   Wong, J ^a   Richardson, D R ^a  

^a UNIVERSITY OF SYDNEY   (Australia)

Author keywords

Cancer; Chelator; Iron; Thiosemicarbazones

Indexed keywords

3 AMINOPICOLINALDEHYDE THIOSEMICARBAZONE; AROYLHYDRAZONE; DEFERASIROX; DEFERIPRONE; DEFEROXAMINE; HYDRAZONE DERIVATIVE; IRON CHELATING AGENT; PYRIDINE DERIVATIVE; TACHPYRIDINE; THIOSEMICARBAZONE DERIVATIVE; UNCLASSIFIED DRUG; 3-AMINOPYRIDINE-2-CARBOXALDEHYDE THIOSEMICARBAZONE; ANTINEOPLASTIC AGENT; IRON;

ANTINEOPLASTIC ACTIVITY; ARTICLE; CHEMICAL STRUCTURE; HYDROPHILICITY; IC 50; IRON CHELATION; IRON DEPLETION; LIPOPHILICITY; MOLECULAR WEIGHT; NEUROBLASTOMA; PRIORITY JOURNAL; ANIMAL; CHEMISTRY; DRUG DESIGN; HUMAN; METABOLISM; NEOPLASMS; PATHOLOGY; STRUCTURE ACTIVITY RELATION; TRANSPORT AT THE CELLULAR LEVEL; TREATMENT OUTCOME;

ANIMALS; ANTINEOPLASTIC AGENTS; BIOLOGICAL TRANSPORT; DRUG DESIGN; HUMANS; IRON; IRON CHELATING AGENTS; MOLECULAR STRUCTURE; NEOPLASMS; PYRIDINES; STRUCTURE-ACTIVITY RELATIONSHIP; THIOSEMICARBAZONES; TREATMENT OUTCOME;

EID: 77954662737     PISSN: 15672018     EISSN: None     Source Type: Journal    
DOI: 10.2174/156720110791560991     Document Type: Article

References (137)

1. Trowbridge, I. S.; Lopez, F. Monoclonal antibody to transfer rinreceptor blocks transferrin binding and inhibits human tumour cellgrowth in vitro. Proc. Natl. Acad. Sci. USA, 1982, 79(4), 1175-1179.
2. Kalinowski, D. S.; Richardson, D. R. The evolution of iron chelators for the treatment of iron overload disease and cancer. Pharmacol. Rev., 2005, 57(4), 547-583.
3. Sartorelli, A. C.; Agrawal, K. C.; Moore, E. C. Mechanism of inhibition of ribonucleoside diphosphate reductase by a-(N)-heterocyclic aldehyde thiosemicarbazones. Biochem. Pharmacol., 1971, 20(11), 3119-3123.
4. Sartorelli, A. C.; Booth, B. A. Inhibition of the growth of sarcoma 180 ascites cells by combinations of inhibitors of nucleic acid biosynthesis and the cupric chelate of kethoxal bis-(thiosemicarbazone). Cancer Res., 1967, 27(9), 1614-1619.
5. Thelander, L.; Reichard, P. Reduction of ribonucleotides. Annu. Rev. Biochem., 1979, 48, 133-158.
6. Green, D. A.; Antholine, W. E.; Wong, S. J.; Richardson, D. R.; Chitambar, C. R. 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. CancerRes., 2001, 7(11), 3574-3579.
7. Richardson, D. R. Iron chelators as therapeutic agents for the treatment of cancer. Crit. Rev.Oncol., Hematol., 2002, 42(3), 267-281.
8. Richardson, D. R.; Kalinowski, D. S.; Lau, S.; Jansson, P. J.; Love-joy, D. B. Cancer cell iron metabolism and the development of potent iron chelators as anti-tumour agents. Biochim. Biophys. Acta, 2009, 1790(7), 702-717.
9. Yu, Y.; Kalinowski, D. S.; Kovacevic, Z.; Siafakas, A. R.; Jansson, P. J.; Stefani, C.; Lovejoy, D. B.; Sharpe, P. C.; Bernhardt, P. V.; Richardson, D. R., Thiosemicarbazones from the old to new: ironchelators that are more than just ribonucleotide reductase inhibitors. J. Med. Chem., 2009, 52(17), 5271-5294.
10. Feun, L.; Modiano, M.; Lee, K.; Mao, J.; Marini, A.; Savaraj, N.; Plezia, P.; Almassian, B.; Colacino, E.; Fischer, J.; MacDonald, S. Phase I and pharmacokinetic study of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone(3-AP) using a single intravenous dose schedule. Cancer Chemother. Pharmacol., 2002, 50(3),223-229.
11. Giles, F. J.; Fracasso, P. M.; Kantarjian, H. M.; Cortes, J. E.; Brown, R. A.; Verstovsek, S.; Alvarado, Y.; Thomas, D. A.; Faderl, S.; Garcia-Manero, G.; Wright, L. P.; Samson, T.; Cahill, A.; Lambert, P.; Plunkett, W.; Sznol, M.; DiPersio, J. F.; Gandhi, V. Phase I and pharmacodynamic study of Triapine, a novel ribonu-cleotide reductase inhibitor, in patients with advanced leukemia. Leuk. Res., 2003, 27(12), 1077-1083.
12. Buss, J. L.; Torti, F. M.; Torti, S. V. The role of iron chelation incancer therapy. Curr. Med. Chem., 2003, 10(12), 1021-1034.
13. Pahl, P. M.; Horwitz, L. D. Cell permeable iron chelators as potential cancer chemotherapeutic agents. Cancer Invest., 2005, 23(8),683-691.
14. Richardson, D. R. Molecular mechanisms of iron uptake by cells and the use of iron chelators for the treatment of cancer. Curr. Med.Chem., 2005, 12(23), 2711-2729.
15. Morgan, E. H. Transferrin biochemistry, physiology and clinical significance. Mol. Aspects Med., 1981,(4), 1-123.
16. Kwok, J. C.; Richardson, D. R. The iron metabolism of neoplastic cells: alterations that facilitate proliferation? Crit. Rev. Oncol. Hematol., 2002, 42(1), 65-78.
17. Richardson, D. R.; Ponka, P. The molecular mechanisms of themetabolism and transport of iron in normal and neoplastic cells. Biochim. Biophys. Acta, 1997, 1331(1), 1-40.
18. Andrews, N. C. The iron transporter DMT1. Int. J. Bioche. Cell.Biol., 1999, 31(10), 991-994.
19. Munro, H. N.; Linder, M. C. Ferritin: structure, biosynthesis, and role in iron metabolism. Physiol. Rev., 1978, 58(2), 317-396.
20. Harrison, P. M.; Arosio, P. The ferritins: molecular properties, iron storage function and cellular regulation. Biochim. Biophys. Acta,1996, 1275(3), 161-203.
21. Le, N. T.; Richardson, D. R. Ferroportin1: a new iron export molecule? Int. J. Biochem. Cell. Biol., 2002, 34(2), 103-108.
22. Hentze, M. W.; Kuhn, L. C. Molecular control of vertebrate iron metabolism: mRNA-based regulatory circuits operated by iron, nitric oxide, and oxidative stress. Proc. Natl. Acad. Sci. USA, 1996, 93(16), 8175-8182.
23. Hentze, M. W.; Muckenthaler, M. U.; Andrews, N. C. Balancing acts: molecular control of mammalian iron metabolism. Cell, 2004,117(3), 285-297.
24. Dunn, L. L.; Rahmanto, Y. S.; Richardson, D. R. Iron uptake and metabolism in the new millennium. Trends Cell. Biol., 2007, 17(2),93-100.
25. Lill, R., Function and biogenesis of iron-sulphur proteins. Nature,2009, 460(7257), 831-838.
26. Le, N. T.; Richardson, D. R. Iron chelators with high antiproliferative activity up-regulate the expression of a growth inhibitory and metastasis suppressor gene: a link between iron metabolism and proliferation. Blood, 2004, 104(9), 2967-2975.
27. Kolberg, M.; Strand, K. R.; Graff, P.; Andersson, K. K. Structure, function, and mechanism of ribonucleotide reductases. Biochim.Biophys. Acta, 2004, 1699(1-2), 1-34.
28. Brodie, C.; Siriwardana, G.; Lucas, J.; Schleicher, R.; Terada, N.; Szepesi, A.; Gelfand, E.; Seligman, P. Neuroblastoma sensitivity togrowth inhibition by deferrioxamine: evidence for a block in G1phase of the cell cycle. Cancer Res., 1993, 53(17), 3968-3975.
29. Darnell, G.; Richardson, D. R. 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, 1999, 94(2), 781-792.
30. Fukuchi, K.; Tomoyasu, S.; Tsuruoka, N.; Gomi, K. Iron deprivation-induced apoptosis in HL-60 cells. FEBS Lett., 1994, 350(1),139-142.
31. Haq, R. U.; Wereley, J. P.; Chitambar, C. R. Induction of apoptosis by iron deprivation in human leukemic CCRF-CEM cells. Exp.Hematol., 1995, 23(5), 428-32.
32. Hoyes, K. P.; Hider, R. C.; Porter, J. B. Cell cycle synchronization and growth inhibition by 3-hydroxypyridin-4-one iron chelators inleukemia cell lines. Cancer Res., 1992, 52(17), 4591-4599.
33. Kovar, J.; Stunz, L. L.; Stewart, B. C.; Kriegerbeckova, K.; Ashman, R. F.; Kemp, J. D. Direct evidence that iron deprivation induces apoptosis in murine lymphoma 38C13. Pathobiology, 1997,65(2), 61-68.
34. Le, N. T.; Richardson, D. R. The role of iron in cell cycle progression and the proliferation of neoplastic cells. Biochim. Biophys.Acta, 2002, 1603(1), 31-46.
35. Nyholm, S.; Mann, G. J.; Johansson, A. G.; Bergeron, R. J.; Graslund, A.; Thelander, L. Role of ribonucleotide reductase in inhibition of mammalian cell growth by potent iron chelators. J. Biol.Chem., 1993, 268(35), 26200-26205.
36. Richardson, D. R.; 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-naphthyl-aldehyde benzoyl hydrazone. Blood, 1997, 89(8), 3025-3038.
37. Lovejoy, D. B.; Richardson, D. R. Novel hybrid iron chelators derived from aroylhydrazones and thiosemicarbazones demonstrateselective antiproliferative activity against tumour cells. Blood,2002, 100(2), 666-676.
38. Yuan, J.; Lovejoy, D. B.; Richardson, D. R. Novel di-2-pyridyl-derived iron chelators with marked and selective antitumour activity: in vitro and in vivo assessment. Blood, 2004, 104(5), 1450-8.
39. Saletta, F., Suryo Rahmanto, Y., Noulsri, E. and Richardson, D.R. Iron Chelator-Mediated Alterations in Gene Expression: Identification of Novel Iron- Regulated Molecules that are Molecular Targets of HIF-1 and p53. Mol. Pharmacol., 2010, 77(3), 443-458.
40. Bai, L.; Merchant, J. L. A role for CITED2, a CBP/p300 interacting protein, in colon cancer cell invasion. FEBS Lett., 2007, 581(30),5904-5910.
41. Choi, B. H.; Kim, C. G.; Bae, Y. S.; Lim, Y.; Lee, Y. H.; Shin, S.Y. p21 Waf1/Cip1 expression by curcumin in U-87MG humanglioma cells: role of early growth response-1 expression. CancerRes., 2008, 68(5), 1369-1377.
42. Zagurovskaya, M.; Shareef, M. M.; Das, A.; Reeves, A.; Gupta, S.; Sudol, M.; Bedford, M. T.; Prichard, J.; Mohiuddin, M.; Ahmed, M. M. EGR-1 forms a complex with YAP-1 and upregulates Baxexpression in irradiated prostate carcinoma cells. Oncogene, 2009,28(8), 1121-1131.
43. Yoshioka, H.; Kamitani, H.; Watanabe, T.; Eling, T. E. Nonsteroidal anti-inflammatory drug-activated gene(NAG-1/GDF15) expres-sion is increased by the histone deacetylase inhibitor trichostatin A.J. Biol. Chem., 2008, 283(48), 33129-33137.
44. Zhou, D.; Chen, B.; Ye, J. J.; Chen, S. A novel crosstalk mechanism between nuclear receptor-mediated and growth factor/Ras-mediated pathways through PNRC-Grb2 interaction. Oncogene, 2004, 23(31), 5394-5404.
45. Takayama, K.; Tsutsumi, S.; Suzuki, T.; Horie-Inoue, K.; Ikeda, K.; Kaneshiro, K.; Fujimura, T.; Kumagai, J.; Urano, T.; Sakaki, Y.; Shirahige, K.; Sasano, H.; Takahashi, S.; Kitamura, T.; Ouchi, Y.; Aburatani, H.; Inoue, S. Amyloid precursor protein is a primary androgen target gene that promotes prostate cancer growth. Cancer,Res., 2009, 69(1), 137-142.
46. Gojo, I.; Tidwell, M. L.; Greer, J.; Takebe, N.; Seiter, K.; Pochron, M. F.; Johnson, B.; Sznol, M.; Karp, J. E. Phase I and pharmacokinetic study of Triapine, a potent ribonucleotide reductase inhibitor,in adults with advanced hematologic malignancies. Leuk. Res., 2007, 31(9), 1165-1173.
47. Mackenzie, M. J.; Saltman, D.; Hirte, H.; Low, J.; Johnson, C.; Pond, G.; Moore, M. J. A Phase II study of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone(3-AP) and gemcitabine in advanced pancreatic carcinoma. A trial of the Princess Margaret hos-pital Phase II consortium. Invest. New Drugs, 2007, 25(6), 553-558.
48. Whitnall, M.; Howard, J.; Ponka, P.; Richardson, D. R. A class of iron chelators with a wide spectrum of potent antitumour activitythat overcomes resistance to chemotherapeutics. Proc. Natl. Acad.Sci. USA, 2006, 103(40), 14901-14906.
49. Dezza, L.; Cazzola, M.; Danova, M.; Carlo-Stella, C.; Bergamaschi, G.; Brugnatelli, S.; Invernizzi, R.; Mazzini, G.; Riccardi, A.; Ascari, E. Effects of desferrioxamine on normal and leukemic human hematopoietic cell growth: in vitro and in vivo studies. Leu-kemia, 1989, 3(2), 104-107.
50. Donfrancesco, A.; De Bernardi, B.; Carli, M.; Mancini, A.; Nigro, M.; De Sio, L.; Casale, F.; Bagnulo, S.; Helson, L.; Deb, G. Defe-roxamine followed by cyclophosphamide, etoposide, carboplatin,thiotepa, induction regimen in advanced neuroblastoma: preliminary results. Italian Neuroblastoma Cooperative Group. Eur. J.Cancer, 1995, 31A(4), 612-615.
51. Donfrancesco, A.; Deb, G.; Dominici, C.; Pileggi, D.; Castello, M.A.; Helson, L. Effects of a single course of deferoxamine in neuro-blastoma patients. Cancer, Res., 1990, 50(16), 4929-4930.
52. Estrov, Z.; Tawa, A.; Wang, X. H.; Dube, I. D.; Sulh, H.; Cohen, A.; Gelfand, E. W.; Freedman, M. H. In vitro and in vivo effects of deferoxamine in neonatal acute leukemia. Blood, 1987, 69(3), 757-761.
53. Becton, D. L.; Bryles, P. Deferoxamine inhibition of human neuroblastoma viability and proliferation. Cancer Res., 1988, 48(24 Pt1), 7189-7192.
54. Blatt, J.; Stitely, S. Antineuroblastoma activity of desferoxamine in human cell lines. Cancer Res., 1987, 47(7), 1749-1750.
55. Liu, J.; Obando, D.; Schipanski, L. G.; Groebler, L. K.; Witting, P.K.; Kalinowski, D. S.; Richardson, D. R.; Codd, R. Conjugates of Desferrioxamine B(DFOB) with Derivatives of Adamantane or with Orally Available Chelators as Potential Agents for Treating Iron Overload. J. Med. Chem., 53(3), 1370-1382.
56. Blatt, J. Deferoxamine in children with recurrent neuroblastoma. Anticancer Res., 1994, 14(5B), 2109-2112.
57. Selig, R. A.; White, L.; Gramacho, C.; Sterling-Levis, K.; Fraser, I.W.; Naidoo, D. Failure of iron chelators to reduce tumour growthin human neuroblastoma xenografts. Cancer Res., 1998, 58(3),473-478.
58. Aouad, F.; Florence, A.; Zhang, Y.; Collins, F.; Henry, C.; Ward, R.; Crichton, R. Evaluation of new iron chelators and their thera-peutic potential. Inorg. Chim. Acta, 2002, 339, 470-480.
59. Wong, C.; Richardson, D. R. Beta-thalassaemia: emergence of new and improved iron chelators for treatment. Int. J. Biochem. Cell.Biol., 2003, 35(7), 1144-1149.
60. Olivieri, N. F.; Brittenham, G. M., Iron-chelating therapy and the treatment of thalassemia. Blood, 1997, 89(3), 739-761.
61. Buss, J. L.; Greene, B. T.; Turner, J.; Torti, F. M.; Torti, S. V. Iron chelators in cancer chemotherapy. Curr. Top Med. Chem., 2004,4(15), 1623-1635.
62. Planalp, R. P.; Przyborowska, A. M.; Park, G.; Ye, N.; Lu, F. H.; Rogers, R. D.; Broker, G. A.; Torti, S. V.; Brechbiel, M. W. Novelcytotoxic chelators that bind iron(II) selectively over zinc(II) underaqueous aerobic conditions. Biochem. Soc. Trans., 2002, 30(4),758-762.
63. Park, G.; Lu, F. H.; Ye, N.; Brechbiel, M. W.; Torti, S. V.; Torti, F.M.; Planalp, R. P. Novel iron complexes and chelators based on cis,cis-1,3,5-triaminocyclohexane: iron-mediated ligand oxidation and biochemical properties. J. Biol. Inorg. Chem., 1998,(3), 449-457.
64. Samuni, A. M.; Krishna, M. C.; DeGraff, W.; Russo, A.; Planalp, R. P.; Brechbiel, M. W.; Mitchell, J. B. Mechanisms underlying thecytotoxic effects of Tachpyr--a novel metal chelator. Biochim. Bio-phys. Acta, 2002, 1571(3), 211-218.
65. Abeysinghe, R. D.; Greene, B. T.; Haynes, R.; Willingham, M. C.; Turner, J.; Planalp, R. P.; Brechbiel, M. W.; Torti, F. M.; Torti, S.V. p53-independent apoptosis mediated by tachpyridine, an anti-cancer iron chelator. Carcinogenesis, 2001, 22(10), 1607-1614.
66. Torti, S. V.; Torti, F. M.; Whitman, S. P.; Brechbiel, M. W.; Park, G.; Planalp, R. P. Tumour cell cytotoxicity of a novel metal chelator. Blood, 1998, 92(4), 1384-1389.
67. Zhao, R.; Planalp, R. P.; Ma, R.; Greene, B. T.; Jones, B. T.; Brechbiel, M. W.; Torti, F. M.; Torti, S. V. Role of zinc and ironchelation in apoptosis mediated by tachpyridine, an anti-cancer iron chelator. Biochem. Pharmacol., 2004, 67(9), 1677-1688.
68. Turner, J.; Koumenis, C.; Kute, T. E.; Planalp, R. P.; Brechbiel, M.W.; Beardsley, D.; Cody, B.; Brown, K. D.; Torti, F. M.; Torti, S.V. Tachpyridine, a metal chelator, induces G2 cell-cycle arrest, ac-tivates checkpoint kinases, and sensitizes cells to ionizing radiation. Blood, 2005, 106(9), 3191-3199.
69. Chaston, T. B.; Lovejoy, D. B.; Watts, R. N.; Richardson, D. R. Examination of the antiproliferative activity of iron chelators: multiple cellular targets and the different mechanism of action of triapine compared with desferrioxamine and the potent pyridoxal isoni-cotinoyl hydrazone analogue 311. Clin. Cancer Res., 2003, 9(1),402-414.
70. Kulp, K. S.; Green, S. L.; Vulliet, P. R. Iron deprivation inhibitscyclin-dependent kinase activity and decreases cyclin D/CDK4 protein levels in asynchronous MDA-MB-453 human breast cancercells. Exp. Cell Res., 1996, 229(1), 60-68.
71. Chong, H. S.; Torti, S. V.; Ma, R.; Torti, F. M.; Brechbiel, M. W. Synthesis and potent antitumour activities of novel 1,3,5-cis,cis-triaminocyclohexane N-pyridyl derivatives. J. Med. Chem., 2004,47(21), 5230-5240.
72. Ponka, P.; Borova, J.; Neuwirt, J.; Fuchs, O. Mobilization of ironfrom reticulocytes. Identification of pyridoxal isonicotinoyl hydrazone as a new iron chelating agent. FEBS Lett., 1979, 97(2), 317-321.
73. Baker, E.; Vitolo, M. L.; Webb, J. Iron chelation by pyridoxal isonicotinoyl hydrazone and analogues in hepatocytes in culture. Biochem. Pharmacol., 1985, 34(17), 3011-3017.
74. Hershko, C.; Avramovici-Grisaru, S.; Link, G.; Gelfand, L.; Sarel, S. Mechanism of in vivo iron chelation by pyridoxal isonicotinoylhydrazone and other imino derivatives of pyridoxal. J. Lab. Clin.Med., 1981, 98(1), 99-108.
75. 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(3), 44344-9.
76. Richardson, D. R.; 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., 1994, 124(5), 660-671.
77. 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(11), 4295-4306.
78. Gao, J.; Richardson, D. R. The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents, IV: The mechanisms involved in inhibiting cell-cycleprogression. Blood, 2001, 98(3), 842-850.
79. Bandyopadhyay, S.; Pai, S. K.; Gross, S. C.; Hirota, S.; Hosobe, S.; Miura, K.; Saito, K.; Commes, T.; Hayashi, S.; Watabe, M.; Watabe, K. The Drg-1 gene suppresses tumour metastasis in prostate cancer. Cancer Res., 2003, 63(8), 1731-1736.
80. Bandyopadhyay, S.; Pai, S. K.; Hirota, S.; Hosobe, S.; Takano, Y.; Saito, K.; Piquemal, D.; Commes, T.; Watabe, M.; Gross, S. C.; Wang, Y.; Ran, S.; Watabe, K. Role of the putative tumour metastasis suppressor gene Drg-1 in breast cancer progression. Oncogene, 2004, 23(33), 5675-81.
81. Kovacevic, Z.; Fu, D.; Richardson, D. R. The iron-regulated metastasis suppressor, Ndrg-1: identification of novel molecular targets. Biochim. Biophys. Acta, 2008, 1783(10), 1981-1992.
82. Kovacevic, Z.; Richardson, D. R. The metastasis suppressor, Ndrg-1: a new ally in the fight against cancer. Carcinogenesis, 2006,27(12), 2355-2366.
83. Stein, S.; Thomas, E. K.; Herzog, B.; Westfall, M. D.; Rocheleau, J. V.; Jackson, R. S., 2nd; Wang, M.; Liang, P. NDRG1 is necessary for p53-dependent apoptosis. J. Biol. Chem., 2004, 279(47),48930-48940.
84. Bernhardt, P. V.; Caldwell, L. M.; Chaston, T. B.; Chin, P.; Richardson, D. R., Cytotoxic iron chelators: characterization of thestructure, solution chemistry and redox activity of ligands and ironcomplexes of the di-2-pyridyl ketone isonicotinoyl hydra-zone(HPKIH) analogues. J. Biol. Inorg. Chem., 2003, 8(8), 866-880.
85. Becker, E. M.; Lovejoy, D. B.; Greer, J. M.; Watts, R.; Richardson, D. R. Identification of the di-pyridyl ketone isonicotinoyl hydra-zone(PKIH) analogues as potent iron chelators and antitumour agents. Br. J. Pharmacol., 2003, 138(5), 819-830.
86. Chaston, T. B.; Watts, R. N.; Yuan, J.; Richardson, D. R. Potent antitumour activity of novel iron chelators derived from di-2-pyridylketone isonicotinoyl hydrazone involves fentonderived freeradical generation. Clin. Cancer Res., 2004, 10(21), 7365-7374.
87. Kovarikova, P.; Mokry, M.; Klimes, J.; Vavrova, K. HPLC studyon stability of pyridoxal isonicotinoyl hydrazone. J. Pharm. Biomed. Anal., 2006, 40(1), 105-112.
88. Kovarikova, P.; Mrkvickova, Z.; Klimes, J. Investigation of the stability of aromatic hydrazones in plasma and related biological material. J. Pharm. Biomed. Anal., 2008, 47(2), 360-370.
89. Stariat, J.; Kovarikova, P.; Klimes, J.; Lovejoy, D. B.; Kalinowski, D. S.; Richardson, D. R. HPLC methods for determination of twonovel thiosemicarbazone anti-cancer drugs(N4mT and Dp44mT) inplasma and their application to in vitro plasma stability of theseagents. J. Chromatogr. B. Anal. Technol. Biomed. Life Sci., 2009,877(3), 316-322.
90. Agrawal, K. C.; Sartorelli, A. C., The chemistry and biological activity of alpha -(N)-heterocyclic carboxaldehyde thiosemicarbazones. Prog. Med. Chem., 1978, 15, 321-56.
91. Antholine, W.; Knight, J.; Whelan, H.; Petering, D. H. Studies of the reaction of 2-formylpyridine thiosemicarbazone and its iron and copper complexes with biological systems. Mol. Pharmacol., 1977,13(1), 89-98.
92. Finch, R. A.; Liu, M.; Grill, S. P.; Rose, W. C.; Loomis, R.; Vasquez, K. M.; Cheng, Y.; Sartorelli, A. C. Triapine(3-aminopyridine-2-carboxaldehyde- thiosemicarbazone): A potentinhibitor of ribonucleotide reductase activity with broad spectrumantitumour activity. Biochem. Pharmacol. 2000, 59(8), 983-991.
93. Garcia-Tojal, J.; Donnadieu, B.; Costes, J. P.; Serra, J. L.; Lezama, L.; Rojo, T. Spectroscopic properties of iron thiosemicarbazone compounds. Structure of [Fe(C7H7N4S)2], E1.25H2O. Inorg.Chim. Acta., 2002,(333), 132-137.
94. Richardson, D. R.; Bernhardt, P. V. 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., 1999, 4(3), 266-273.
95. Arion, V. B.; Jakupec, M. A.; Galanski, M.; Unfried, P.; Keppler, B. K. Synthesis, structure, spectroscopic and in vitro antitumour studies of a novel gallium(III) complex with 2-acetylpyridine(4)N-dimethylthio semicarbazone. J. Inorg. Biochem., 2002, 91(1), 298-305.
96. Mohan, M.; Agarawal, A.; Jha, N. K. Synthesis, characterization, and antitumour properties of some metal complexes of 2,6-diacetylpyridine bis(N4-azacyclic thiosemicarbazones). J. Inorg.Biochem., 1988, 34(1), 41-54.
97. Cooper, C. E.; Lynagh, G. R.; Hoyes, K. P.; Hider, R. C.; Cammack, R.; Porter, J. B. The relationship of intracellular iron chelation to the inhibition and regeneration of human ribonucleotide reductase. J. Biol. Chem., 1996, 271(34), 20291-20299.
98. Shao, J.; Zhou, B.; Di Bilio, A. J.; Zhu, L.; Wang, T.; Qi, C.; Shih, J.; Yen, Y. A Ferrous-Triapine complex mediates formation of reactive oxygen species that inactivate human ribonucleotide reductase. Mol. Cancer Ther., 2006, 5(3), 586-592.
99. Kowol, C. R.; Trondl, R.; Heffeter, P.; Arion, V. B.; Jakupec, M.A.; Roller, A.; Galanski, M.; Berger, W.; Keppler, B. K. Impact of Metal Coordination on Cytotoxicity of 3-Aminopyridine-2-carboxaldehyde Thiosemicarbazone(Triapine) and Novel Insightsinto Terminal Dimethylation. J. Med. Chem., 2009. [Epub ahead of Print].
100. Finch, R. A.; Liu, M. C.; Cory, A. H.; Cory, J. G.; Sartorelli, A. C.Triapine(3-aminopyridine-2-carboxaldehyde thiosemicarbazone; 3-AP): an inhibitor of ribonucleotide reductase with antineoplasticactivity. Adv. Enzyme Regul., 1999, 39, 3-12.
101. Attia, S.; Kolesar, J.; Mahoney, M. R.; Pitot, H. C.; Laheru, D.; Heun, J.; Huang, W.; Eickhoff, J.; Erlichman, C.; Holen, K. D. Aphase 2 consortium(P2C) trial of 3-aminopyridine-2-carbox-aldehyde thiosemicarbazone(3-AP) for advanced adenocarcinoma of the pancreas. Invest New Drugs, 2008, 26(4), 369-379.
102. Knox, J. J.; Hotte, S. J.; Kollmannsberger, C.; Winquist, E.; Fisher, B.; Eisenhauer, E. A. Phase II study of Triapine in patients with metastatic renal cell carcinoma: a trial of the National Cancer Institute of Canada Clinical Trials Group(NCIC IND.161). Invest. NewDrugs, 2007, 25(5), 471-477.
103. Nutting, C. M.; van Herpen, C. M.; Miah, A. B.; Bhide, S. A.; Machiels, J. P.; Buter, J.; Kelly, C.; de Raucourt, D.; Harrington, K.J. Phase II study of 3-AP Triapine in patients with recurrent or metastatic head and neck squamous cell carcinoma. Ann. Oncol.,2009, 20(7), 1275-1279.
104. Wadler, S.; Makower, D.; Clairmont, C.; Lambert, P.; Fehn, K.; Sznol, M. Phase I and pharmacokinetic study of the ribonucleotidereductase inhibitor, 3-aminopyridine-2-carboxaldehyde thiosemi-carbazone, administered by 96-hour intravenous continuous infusion. J. Clin. Oncol., 2004, 22(9), 1553-1563.
105. Traynor, A. M.; Lee, J. W.; Bayer, G. K.; Tate, J. M.; Thomas, S.P.; Mazurczak, M.; Graham, D. L.; Kolesar, J. M.; Schiller, J. H. A phase II trial of Triapine(R)(NSC# 663249) and gemcitabine assecond line treatment of advanced non-small cell lung cancer:Eastern Cooperative Oncology Group Study 1503. Invest. New Drugs, 2010, 28(1), 91-7.
106. Yen, Y.; Margolin, K.; Doroshow, J.; Fishman, M.; Johnson, B.; Clairmont, C.; Sullivan, D.; Sznol, M. A phase I trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone in combina-tion with gemcitabine for patients with advanced cancer. Cancer,Chemother. Pharmacol., 2004, 54(4), 331-342.
107. Schelman, W. R.; Morgan-Meadows, S.; Marnocha, R.; Lee, F.; Eickhoff, J.; Huang, W.; Pomplun, M.; Jiang, Z.; Alberti, D.; Kolesar, J. M.; Ivy, P.; Wilding, G.; Traynor, A. M. A phase I study ofTriapine in combination with doxorubicin in patients with ad-vanced solid tumours. Cancer Chemother. Pharmacol., 2009,63(6), 1147-1156.
108. Odenike, O. M.; Larson, R. A.; Gajria, D.; Dolan, M. E.; Delaney, S. M.; Karrison, T. G.; Ratain, M. J.; Stock, W. Phase I study of theribonucleotide reductase inhibitor 3-aminopyridine-2-carbox-aldehyde-thiosemicarbazone(3-AP) in combination with high dosecytarabine in patients with advanced myeloid leukemia. Invest.New Drugs, 2008, 26(3), 233-239.
109. Yee, K. W.; Cortes, J.; Ferrajoli, A.; Garcia-Manero, G.; Verstovsek, S.; Wierda, W.; Thomas, D.; Faderl, S.; King, I.; O'BrienS, M.; Jeha, S.; Andreeff, M.; Cahill, A.; Sznol, M.; Giles, F. J. Triapine and cytarabine is an active combination in patients with acute leukemia or myelodysplastic syndrome. Leuk. Res., 2006,30(7), 813-22.
110. Karp, J. E.; Giles, F. J.; Gojo, I.; Morris, L.; Greer, J.; Johnson, B.; Thein, M.; Sznol, M.; Low, J. A phase I study of the novel ribonu-cleotide reductase inhibitor 3-aminopyridine-2-carboxaldehydethiosemicarbazone(3-AP, Triapine) in combination with the nucleoside analog fludarabine for patients with refractory acute leukemias and aggressive myeloproliferative disorders. Leuk. Res.,2008, 32(1), 71-77.
111. van der Donk, W. A.; Yu, G.; Perez, L.; Sanchez, R. J.; Stubbe, J.; Samano, V.; Robins, M. J. Detection of a new substrate-derivedradical during inactivation of ribonucleotide reductase from Escherichia coli by gemcitabine 5'-diphosphate. Biochemistry, 1998,37(18), 6419-6426.
112. Sigmond, J.; Kamphuis, J. A.; Laan, A. C.; Hoebe, E. K.; Bergman, A. M.; Peters, G. J., The synergistic interaction of gemcitabine and cytosine arabinoside with the ribonucleotide reductase inhibitor triapine is schedule dependent. Biochem. Pharmacol., 2007, 73(10),1548-1557.
113. Ma, B.; Goh, B. C.; Tan, E. H.; Lam, K. C.; Soo, R.; Leong, S. S.; Wang, L. Z.; Mo, F.; Chan, A. T.; Zee, B.; Mok, T. A multicenterphase II trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone(3-AP, Triapine) and gemcitabine in advanced non-small-celllung cancer with pharmacokinetic evaluation using peripheralblood mononuclear cells. Invest. New Drugs 2008, 26(2), 169-173.
114. Chun, H. G.; Leyland-Jones, B.; Cheson, B. D., Fludarabine phosphate: a synthetic purine antimetabolite with significant activityagainst lymphoid malignancies. J. Clin. Oncol., 1991, 9(1), 175-188.
115. Richardson, D. R.; Sharpe, P. C.; Lovejoy, D. B.; Senaratne, D.; Kalinowski, D. S.; Islam, M.; Bernhardt, P. V. Dipyridyl thiosemicarbazone chelators with potent and selective antitumour activityform iron complexes with redox activity. J. Med. Chem., 2006,49(22), 6510-6521.
116. Noulsri, E.; Richardson, D. R.; Lerdwana, S.; Fucharoen, S.; Yamagishi, T.; Kalinowski, D. S.; Pattanapanyasat, K. Antitumour activity and mechanism of action of the iron chelator, Dp44mT,against leukemic cells. Am. J. Hematol., 2009, 84(3), 170-176.
117. Pullarkat, V. Objectives of iron chelation therapy in myelodysplas-tic syndromes: more than meets the eye? Blood, 2009, 114(26),5251-5255.
118. Bernhardt, P. V.; Sharpe, P. C.; Islam, M.; Lovejoy, D. B.; Kali-nowski, D. S.; Richardson, D. R. Iron chelators of the dipyridylketone thiosemicarbazone class: precomplexation and transmetalationeffects on anticancer activity. J. Med. Chem., 2009, 52(2), 407-415.
119. Harris, E. D., A requirement for copper in angiogenesis. Nutr. Rev.,2004, 62(2), 60-64.
120. Kalinowski, D. S.; Sharpe, P. C.; Bernhardt, P. V.; Richardson, D.R. Design, synthesis, and characterization of new iron chelators with anti-proliferative activity: structure-activity relationships of novel thiohydrazone analogues. J. Med. Chem., 2007, 50(24),6212-6225.
121. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv.Drug Deliv. Rev., 2001, 46(1-3), 3-26.
122. Ivan, M.; Kondo, K.; Yang, H.; Kim, W.; Valiando, J.; Ohh, M.; Salic, A.; Asara, J. M.; Lane, W. S.; Kaelin, W. G., Jr. HIF alphatargeted for VHL-mediated destruction by proline hydroxylation:implications for O2 sensing. Science, 2001, 292(5516), 464-468.
123. Jaakkola, P.; Mole, D. R.; Tian, Y. M.; Wilson, M. I.; Gielbert, J.; Gaskell, S. J.; Kriegsheim, A.; Hebestreit, H. F.; Mukherji, M.; Schofield, C. J.; Maxwell, P. H.; Pugh, C. W.; Ratcliffe, P. J. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science, 2001,292(5516), 468-472.
124. Pugh, C. W.; Ratcliffe, P. J. Regulation of angiogenesis by hypoxia: role of the HIF system. Nat. Med., 2003, 9(6), 677-684.
125. Ratcliffe, P. J.; Pugh, C. W.; Maxwell, P. H. Targeting tumours through the HIF system. Nat Med., 2000, 6(12), 1315-1316.
126. Yu, F.; White, S. B.; Zhao, Q.; Lee, F. S. HIF-1alpha binding toVHL is regulated by stimulus-sensitive proline hydroxylation. Proc. Natl. Acad. Sci., USA., 2001, 98(17), 9630-9635.
127. Masson, N.; Willam, C.; Maxwell, P. H.; Pugh, C. W.; Ratcliffe, P.J., Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation. EMBO J., 2001, 20(18), 5197-5206.
128. Wenger, R. H. Mammalian oxygen sensing, signalling and generegulation. J. Exp. Biol., 2000, 203(Pt 8), 1253-1263.
129. Forsythe, J. A.; Jiang, B. H.; Iyer, N. V.; Agani, F.; Leung, S. W.; Koos, R. D.; Semenza, G. L. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol. Cell Biol., 1996, 16(9), 4604-4613.
130. Krieg, M.; Haas, R.; Brauch, H.; Acker, T.; Flamme, I.; Plate, K.H. Up-regulation of hypoxia-inducible factors HIF-1alpha and HIF-2alpha under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumour suppressor gene loss of function. Oncogene,2000, 19(48), 5435-5443.
131. Palmer, L. A.; Semenza, G. L.; Stoler, M. H.; Johns, R. A. Hypoxiainduces type II NOS gene expression in pulmonary artery endothelial cells via HIF-1. Am. J. Physiol., 1998, 274(2 Pt 1), L212-219.
132. Maruyama, Y.; Ono, M.; Kawahara, A.; Yokoyama, T.; Basaki, Y.; Kage, M.; Aoyagi, S.; Kinoshita, H.; Kuwano, M. Tumour growths uppression in pancreatic cancer by a putative metastasis suppressor gene Cap43/NDRG1/Drg-1 through modulation of angiogenesis. Cancer Res., 2006, 66(12), 6233-6242.
133. Hodges, Y. K.; Reese, S. M.; Pahl, P. M.; Horwitz, L. D., Paradoxical effects of iron chelation on growth of vascular endothelialcells. J. Cardiovasc. Pharmacol., 2005, 45(6), 539-544.
134. Fukuchi, K.; Tomoyasu, S.; Watanabe, H.; Kaetsu, S.; Tsuruoka, N.; Gomi, K., Iron deprivation results in an increase in p53 expression. Biol. Chem. Hoppe. Seyler, 1995, 376(10), 627-630.
135. Liang, S. X.; Richardson, D. R. The effect of potent iron chelatorson the regulation of p53: examination of the expression, localization and DNA-binding activity of p53 and the trans activation of WAF1. Carcinogenesis, 2003, 24(10), 1601-1614.
136. Sun, Y.; Bian, J.; Wang, Y.; Jacobs, C., Activation of p53 transcriptional activity by 1,10-phenanthroline, a metal chelator and redox sensitive compound. Oncogene, 1997, 14(4), 385-393.
137. Le, N. T.; Richardson, D. R. Potent iron chelators increase them RNA levels of the universal cyclin-dependent kinase inhibitorp21(CIP1/WAF1), but paradoxically inhibit its translation: a potential mechanism of cell cycle dysregulation. Carcinogenesis, 2003,24(6), 1045-1058.