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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
https://doi.org/10.1021/jm0606342
Copyright © 2006 American Chemical Society
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Abstract

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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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  55. Zhang-Xu He, Jin-Ling Huo, Yun-Peng Gong, Qi An, Xin Zhang, Hui Qiao, Fei-Fei Yang, Xin-Hui Zhang, Le-Min Jiao, Hong-Min Liu, Li-Ying Ma, Wen Zhao. Design, synthesis and biological evaluation of novel thiosemicarbazone-indole derivatives targeting prostate cancer cells. European Journal of Medicinal Chemistry 2021, 210 , 112970. https://doi.org/10.1016/j.ejmech.2020.112970
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  57. Junmiao Wu, Tongfu Yang, Xiaojun Wang, Wenjuan Li, Min Pang, Hongbin Sun, Hong Liang, Feng Yang. Development of a multi-target anticancer Sn( ii ) pyridine-2-carboxaldehyde thiosemicarbazone complex. Dalton Transactions 2021, 88 https://doi.org/10.1039/D1DT01272J
  58. Éva A. Enyedy, Nóra V. May, Veronika F. S. Pape, Petra Heffeter, Gergely Szakács, Bernhard K. Keppler, Christian R. Kowol. Complex formation and cytotoxicity of Triapine derivatives: a comparative solution study on the effect of the chalcogen atom and NH-methylation. Dalton Transactions 2020, 49 (46) , 16887-16902. https://doi.org/10.1039/D0DT03465G
  59. Silvia Paukovcekova, Jan Skoda, Jakub Neradil, Erika Mikulenkova, Petr Chlapek, Jaroslav Sterba, Des R. Richardson, Renata Veselska. Novel Thiosemicarbazones Sensitize Pediatric Solid Tumor Cell-Types to Conventional Chemotherapeutics through Multiple Molecular Mechanisms. Cancers 2020, 12 (12) , 3781. https://doi.org/10.3390/cancers12123781
  60. S. Krishan, S. Sahni, D.R. Richardson. The anti-tumor agent, Dp44mT, promotes nuclear translocation of TFEB via inhibition of the AMPK-mTORC1 axis. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 2020, 1866 (12) , 165970. https://doi.org/10.1016/j.bbadis.2020.165970
  61. Kyung Chan Park, Des R. Richardson. The c-MET oncoprotein: Function, mechanisms of degradation and its targeting by novel anti-cancer agents. Biochimica et Biophysica Acta (BBA) - General Subjects 2020, 1864 (10) , 129650. https://doi.org/10.1016/j.bbagen.2020.129650
  62. Waleska R. P. Costa, Rafael A. C. Souza, Victor M. Deflon, Carolina G. Oliveira. Preparation, structural characterization, voltammetry and Hirshfeld surface analysis of homoleptic iron(III) thiosemicarbazone complexes. Transition Metal Chemistry 2020, 45 (7) , 511-521. https://doi.org/10.1007/s11243-020-00404-w
  63. A.M. Sólimo, M.C. Soraires Santacruz, S. Vanzulli, O. Coggiola, E. Bal de Kier Joffé, L. Finkielsztein, M.A. Callero. Anti-metastatic action of an N4-aryl substituted thiosemicarbazone on advanced triple negative breast cancer.. Heliyon 2020, 6 (10) , e05161. https://doi.org/10.1016/j.heliyon.2020.e05161
  64. Kyung Chan Park, Jasmina Paluncic, Zaklina Kovacevic, Des R. Richardson. Pharmacological targeting and the diverse functions of the metastasis suppressor, NDRG1, in cancer. Free Radical Biology and Medicine 2020, 157 , 154-175. https://doi.org/10.1016/j.freeradbiomed.2019.05.020
  65. S. Chiang, M.L.H. Huang, D.R. Richardson. Treatment of dilated cardiomyopathy in a mouse model of Friedreich’s ataxia using N-acetylcysteine and identification of alterations in microRNA expression that could be involved in its pathogenesis. Pharmacological Research 2020, 159 , 104994. https://doi.org/10.1016/j.phrs.2020.104994
  66. Miljan N. M. Milunović, Oleg Palamarciuc, Angela Sirbu, Sergiu Shova, Dan Dumitrescu, Dana Dvoranová, Peter Rapta, Tatsiana V. Petrasheuskaya, Eva A. Enyedy, Gabriella Spengler, Marija Ilic, Harald H. Sitte, Gert Lubec, Vladimir B. Arion. Insight into the Anticancer Activity of Copper(II) 5-Methylenetrimethylammonium-Thiosemicarbazonates and Their Interaction with Organic Cation Transporters. Biomolecules 2020, 10 (9) , 1213. https://doi.org/10.3390/biom10091213
  67. Kateryna Ohui, Iryna Stepanenko, Iuliana Besleaga, Maria V. Babak, Radu Stafi, Denisa Darvasiova, Gerald Giester, Vivien Pósa, Eva A. Enyedy, Daniel Vegh, Peter Rapta, Wee Han Ang, Ana Popović-Bijelić, Vladimir B. Arion. Triapine Derivatives Act as Copper Delivery Vehicles to Induce Deadly Metal Overload in Cancer Cells. Biomolecules 2020, 10 (9) , 1336. https://doi.org/10.3390/biom10091336
  68. Mathilde Bouché, Cécilia Hognon, Stéphanie Grandemange, Antonio Monari, Philippe C. Gros. Recent advances in iron-complexes as drug candidates for cancer therapy: reactivity, mechanism of action and metabolites. Dalton Transactions 2020, 49 (33) , 11451-11466. https://doi.org/10.1039/D0DT02135K
  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. https://doi.org/10.1016/j.bbagen.2020.129625
  70. C.K. Holley, S. Majd. Examining the Anti-Tumor Activity of Dp44mT-Loaded Nanoparticles In Vitro. 2020,,, 5029-5032. https://doi.org/10.1109/EMBC44109.2020.9176197
  71. Bhushan Shakya, Paras Nath Yadav. Thiosemicarbazones as Potent Anticancer Agents and their Modes of Action. Mini-Reviews in Medicinal Chemistry 2020, 20 (8) , 638-661. https://doi.org/10.2174/1389557519666191029130310
  72. Winaki P. Sohtun, Themmila Khamrang, Arunachalam Kannan, Gowdhami Balakrishnan, Dhandayutham Saravanan, Mohammad Abdulkader Akhbarsha, Marappan Velusamy, Mallayan Palaniandavar. Iron(III) bis‐complexes of Schiff bases of S ‐methyldithiocarbazates: Synthesis, structure, spectral and redox properties and cytotoxicity. Applied Organometallic Chemistry 2020, 34 (5) https://doi.org/10.1002/aoc.5593
  73. Bi-Qun Zou, Xiao-Ling Huang, Qi-Pin Qin, Zhen-Feng Wang, Xue-Yu Wu, Ming-Xiong Tan, Hong Liang. Transition metal complexes with 6,7-dichloro-5,8-quinolinedione as mitochondria-targeted anticancer agents. Polyhedron 2020, 181 , 114482. https://doi.org/10.1016/j.poly.2020.114482
  74. S. Krishan, S. Sahni, L.Y.W. Leck, P.J. Jansson, D.R. Richardson. Regulation of autophagy and apoptosis by Dp44mT-mediated activation of AMPK in pancreatic cancer cells. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 2020, 1866 (5) , 165657. https://doi.org/10.1016/j.bbadis.2019.165657
  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. https://doi.org/10.1111/bph.14963
  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. https://doi.org/10.1016/j.poly.2019.114333
  77. Soheila Jenabi Sardroud, Seyed Abolfazl Hosseini-Yazdi, Majid Mahdavi, Morgane Poupon, Eliska Skorepova. Synthesis, characterization and in vitro evaluation of anticancer activity of a new water-soluble thiosemicarbazone ligand and its complexes. Polyhedron 2020, 175 , 114218. https://doi.org/10.1016/j.poly.2019.114218
  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. https://doi.org/10.1074/jbc.RA119.011341
  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. https://doi.org/10.1039/C9DT03557E
  80. Merve Ertas, Zafer Sahin, Emre F. Bulbul, Ceysu Bender, Sevde N. Biltekin, Barkin Berk, Leyla Yurttas, Aysu M. Nalbur, Hayati Celik, Şeref Demirayak. Potent ribonucleotide reductase inhibitors: Thiazole‐containing thiosemicarbazone derivatives. Archiv der Pharmazie 2019, 352 (11) , 1900033. https://doi.org/10.1002/ardp.201900033
  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. https://doi.org/10.1093/jac/dkz290
  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. https://doi.org/10.1016/j.bbadis.2019.04.007
  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. https://doi.org/10.1093/carcin/bgy178
  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. https://doi.org/10.1016/j.bbadis.2019.02.008
  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. https://doi.org/10.1016/j.ejmech.2019.03.027
  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. https://doi.org/10.2174/0929867324666170705120809
  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. https://doi.org/10.1089/ars.2017.7387
  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. https://doi.org/10.1089/ars.2017.7487
  89. Sharleen V. Menezes, Zaklina Kovacevic, Des R. Richardson. The metastasis suppressor NDRG1 down-regulates the epidermal growth factor receptor via a lysosomal mechanism by up-regulating mitogen-inducible gene 6. Journal of Biological Chemistry 2019, 294 (11) , 4045-4064. https://doi.org/10.1074/jbc.RA118.006279
  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. https://doi.org/10.1080/15257770.2018.1508691
  91. Hee-Yun Kim, Na-Ra Han, Hyung-Min Kim, Hyun-Ja Jeong. The Iron Chelator and Anticancer Agent Dp44mT Relieves Allergic Inflammation in Mice With Allergic Rhinitis. Inflammation 2018, 41 (5) , 1744-1754. https://doi.org/10.1007/s10753-018-0817-4
  92. Kyung Chan Park, Sharleen V. Menezes, Danuta S. Kalinowski, Sumit Sahni, Patric J. Jansson, Zaklina Kovacevic, Des R. Richardson. Identification of differential phosphorylation and sub-cellular localization of the metastasis suppressor, NDRG1. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 2018, 1864 (8) , 2644-2663. https://doi.org/10.1016/j.bbadis.2018.04.011
  93. Dawid Zych, Aneta Slodek, Stanisław Krompiec, Katarzyna Malarz, Anna Mrozek-Wilczkiewicz, Robert Musiol. 4′-Phenyl-2,2′:6′,2′′-terpyridine Derivatives Containing 1-Substituted-2,3-Triazole Ring: Synthesis, Characterization and Anticancer Activity. ChemistrySelect 2018, 3 (24) , 7009-7017. https://doi.org/10.1002/slct.201801204
  94. Liangfu Zhou, Bin Zhao, Lixiu Zhang, Shenghang Wang, Dandan Dong, Huanhuan Lv, Peng Shang. Alterations in Cellular Iron Metabolism Provide More Therapeutic Opportunities for Cancer. International Journal of Molecular Sciences 2018, 19 (5) , 1545. https://doi.org/10.3390/ijms19051545
  95. Marta Rejmund, Anna Mrozek-Wilczkiewicz, Katarzyna Malarz, Monika Pyrkosz-Bulska, Kamila Gajcy, Mieczyslaw Sajewicz, Robert Musiol, Jaroslaw Polanski, . Piperazinyl fragment improves anticancer activity of Triapine. PLOS ONE 2018, 13 (4) , e0188767. https://doi.org/10.1371/journal.pone.0188767
  96. Katarzyna Malarz, Anna Mrozek-Wilczkiewicz, Maciej Serda, Marta Rejmund, Jaroslaw Polanski, Robert Musiol. The role of oxidative stress in activity of anticancer thiosemicarbazones. Oncotarget 2018, 9 (25) , 17689-17710. https://doi.org/10.18632/oncotarget.24844
  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. https://doi.org/10.1016/j.bbagen.2017.10.009
  98. Orsolya Dömötör, Nóra V. May, Karla Pelivan, Tamás Kiss, Bernhard K. Keppler, Christian R. Kowol, Éva A. Enyedy. A comparative study of α- N -pyridyl thiosemicarbazones: Spectroscopic properties, solution stability and copper(II) complexation. Inorganica Chimica Acta 2018, 472 , 264-275. https://doi.org/10.1016/j.ica.2017.07.001
  99. Z. Moradi-Shoeili, M. Zare. The Effect of Substituents on Catalytic Performance of bis-Thiosemicarbazone Mo(VI) Complexes: Synthesis and Spectroscopic, Electrochemical, and Functional Properties. Kinetics and Catalysis 2018, 59 (2) , 203-210. https://doi.org/10.1134/S002315841802012X
  100. Carolane M. Almeida, Gabriel P. Nascimento, Kelly G. Magalhães, Bernardo A. Iglesias, Claudia C. Gatto. Crystal structures, DNA-binding ability and influence on cellular viability of gold(I) complexes of thiosemicarbazones. Journal of Coordination Chemistry 2018, 71 (4) , 502-519. https://doi.org/10.1080/00958972.2018.1435869
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