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Dipyridyl Thiosemicarbazone Chelators with Potent and Selective Antitumor Activity Form Iron Complexes with Redox Activity

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Iron Metabolism and Chelation Program, Department of Pathology, University of Sydney, Sydney, New South Wales 2006, Australia, Iron Metabolism and Chelation Program, Children's Cancer Institute Australia for Medical Research, Randwick, Sydney, New South Wales 2031, Australia, and Centre for Metals in Biology, Department of Chemistry, University of Queensland, Brisbane 4072, Australia
Cite this: J. Med. Chem. 2006, 49, 22, 6510–6521
Publication Date (Web):September 29, 2006
Copyright © 2006 American Chemical Society
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There has been much interest in the development of iron (Fe) chelators for the treatment of cancer. We developed a series of di-2-pyridyl ketone thiosemicarbazone (HDpT) ligands which show marked and selective antitumor activity in vitro and in vivo. In this study, we assessed chemical and biological properties of these ligands and their Fe complexes in order to understand their marked activity. This included examination of their solution chemistry, electrochemistry, ability to mediate redox reactions, and antiproliferative activity against tumor cells. The higher antiproliferative efficacy of the HDpT series of chelators relative to the related di-2-pyridyl ketone isonicotinoyl hydrazone (HPKIH) analogues can be ascribed, in part, to the redox potentials of their Fe complexes which lead to the generation of reactive oxygen species. The most effective HDpT ligands as antiproliferative agents possess considerable lipophilicity and were shown to be charge neutral at physiological pH, allowing access to intracellular Fe pools.


 Authors for correspondence. D.R.R. (biology):  phone, +61-2-9036-6548; fax, +61-2-9036-6549; e-mail, [email protected] P.V.B. (chemistry):  phone, +61-7-3365-4266; fax, +61-7-3365-4299; e-mail, [email protected]

 University of Sydney.


 Children's Cancer Institute Australia for Medical Research.

 University of Queensland.

Abbreviations:  3-AP, 3-aminopyridine-2-carboxaldehyde-thiosemicarbazone; DFO, desferrioxamine; DOX, doxorubicin; HDpT, di-2-pyridyl ketone thiosemicarbazone; HDp4aT, di-2-pyridyl ketone 4-allyl-3-thiosemicarbazone; HDp4eT, di-2-pyridyl ketone 4-ethyl-3-thiosemicarbazone; HDp4mT, di-2-pyridyl ketone 4-methyl-3-thiosemicarbazone; HDp44mT, di-2-pyridyl ketone 4,4-dimethyl-3-thiosemicarbazone; HDp4pT, di-2-pyridyl ketone 4-phenyl-3-thiosemicarbazone; H2NIH, 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone; H2NT, 2-hydroxy-1-naphthylaldehyde thiosemicarbazone; HPKIH, di-2-pyridyl ketone isonicotinoyl hydrazone; H2PIH, pyridoxal isonicotinoyl hydrazone; IBE, iron-binding equivalent; OC, open-circular; ROS, reactive oxygen species; SC, supercoiled; Tf, transferrin; TfR1, transferrin receptor 1.

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  69. Sumit Sahni, Josef Gillson, Kyung Chan Park, Shannon Chiang, Lionel Yi Wen Leck, Patric J. Jansson, Des R. Richardson. NDRG1 suppresses basal and hypoxia-induced autophagy at both the initiation and degradation stages and sensitizes pancreatic cancer cells to lysosomal membrane permeabilization. Biochimica et Biophysica Acta (BBA) - General Subjects 2020, 1864 (8) , 129625.
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  75. Zhixuan Wu, Duraippandi Palanimuthu, Nady Braidy, Nor Hawani Salikin, Suhelen Egan, Michael L.H. Huang, Des R. Richardson. Novel multifunctional iron chelators of the aroyl nicotinoyl hydrazone class that markedly enhance cellular NAD + /NADH ratios. British Journal of Pharmacology 2020, 177 (9) , 1967-1987.
  76. B. Amritha, O. Manaf, M. Nethaji, A. Sujith, M.R. Prathapachandra Kurup, Suni Vasudevan. Mn(II) complex of a di-2-pyridyl ketone-N(4)-substituted thiosemicarbazone: Versatile biological properties and naked-eye detection of Fe2+ and Ru3+ ions. Polyhedron 2020, 178 , 114333.
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  78. Kyung Chan Park, Bekesho Geleta, Lionel Yi Wen Leck, Jasmina Paluncic, Shannon Chiang, Patric J. Jansson, Zaklina Kovacevic, Des R. Richardson. Thiosemicarbazones suppress expression of the c-Met oncogene by mechanisms involving lysosomal degradation and intracellular shedding. Journal of Biological Chemistry 2020, 295 (2) , 481-503.
  79. Miguel A. Gonzálvez, Andrés G. Algarra, Manuel G. Basallote, Paul V. Bernhardt, María J. Fernández-Trujillo, Manuel Martínez. Proton-assisted air oxidation mechanisms of iron( ii ) bis-thiosemicarbazone complexes at physiological pH: a kinetico-mechanistic study. Dalton Transactions 2019, 48 (44) , 16578-16587.
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  81. Christopher J Parkinson, Geoffrey W Birrell, Marina Chavchich, Donna Mackenzie, Richard K Haynes, Carmen de Kock, Des R Richardson, Michael D Edstein. Development of pyridyl thiosemicarbazones as highly potent agents for the treatment of malaria after oral administration. Journal of Antimicrobial Chemotherapy 2019, 74 (10) , 2965-2973.
  82. A.M. Merlot, G.M. Porter, S. Sahni, E.G. Lim, P. Peres, D.R. Richardson. The metastasis suppressor, NDRG1, differentially modulates the endoplasmic reticulum stress response. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 2019, 1865 (9) , 2094-2110.
  83. Sharleen V Menezes, Leyla Fouani, Michael L H Huang, Bekesho Geleta, Sanaz Maleki, Alexander Richardson, Des R Richardson, Zaklina Kovacevic. The metastasis suppressor, NDRG1, attenuates oncogenic TGF-β and NF-κB signaling to enhance membrane E-cadherin expression in pancreatic cancer cells. Carcinogenesis 2019, 40 (6) , 805-818.
  84. Sumit Sahni, Kyung Chan Park, Zaklina Kovacevic, Des R. Richardson. Two mechanisms involving the autophagic and proteasomal pathways process the metastasis suppressor protein, N-myc downstream regulated gene 1. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 2019, 1865 (6) , 1361-1378.
  85. Anna Mrozek-Wilczkiewicz, Katarzyna Malarz, Marta Rejmund, Jaroslaw Polanski, Robert Musiol. Anticancer activity of the thiosemicarbazones that are based on di-2-pyridine ketone and quinoline moiety. European Journal of Medicinal Chemistry 2019, 171 , 180-194.
  86. Angelica M. Merlot, Danuta S. Kalinowski, Zaklina Kovacevic, Patric J. Jansson, Sumit Sahni, Michael L.-H. Huang, Darius J.R. Lane, Hiu Lok, Des R. Richardson. Exploiting Cancer Metal Metabolism using Anti-Cancer Metal- Binding Agents. Current Medicinal Chemistry 2019, 26 (2) , 302-322.
  87. Leyla Fouani, Zaklina Kovacevic, Des R. Richardson. Targeting Oncogenic Nuclear Factor Kappa B Signaling with Redox-Active Agents for Cancer Treatment. Antioxidants & Redox Signaling 2019, 30 (8) , 1096-1123.
  88. Petra Heffeter, Veronika F.S. Pape, Éva A. Enyedy, Bernhard K. Keppler, Gergely Szakacs, Christian R. Kowol. Anticancer Thiosemicarbazones: Chemical Properties, Interaction with Iron Metabolism, and Resistance Development. Antioxidants & Redox Signaling 2019, 30 (8) , 1062-1082.
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  90. Chittanahalli N. Sudhamani, Halehatty S. Bhojya Naik, Kalligundi R. Sangeetha Gowda, Dugganna Girija, Manju Giridhar. DNA binding, prominent photonuclease activity and antibacterial PDT of cobalt(II) complexes of phenanthroline based photosensitizers. Nucleosides, Nucleotides & Nucleic Acids 2018, 37 (10) , 546-562.
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  97. Rayan S. Moussa, Zaklina Kovacevic, Dong-Hun Bae, Darius J.R. Lane, Des R. Richardson. Transcriptional regulation of the cyclin-dependent kinase inhibitor, p21 CIP1/WAF1 , by the chelator, Dp44mT. Biochimica et Biophysica Acta (BBA) - General Subjects 2018, 1862 (3) , 761-774.
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