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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.

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     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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    67. Ming Jiang, Tongfu Yang, Yong Chu, Zhenlei Zhang, Hongbin Sun, Hong Liang, Feng Yang. Design of a novel Pt( ii ) complex to reverse cisplatin-induced resistance in lung cancer via a multi-mechanism. Dalton Transactions 2022, 51 (13) , 5257-5270.
    68. Bekesho Geleta, Faten S. Tout, Syer Choon Lim, Sumit Sahni, Patric J. Jansson, Minoti V. Apte, Des R. Richardson, Žaklina Kovačević. Targeting Wnt/tenascin C-mediated cross talk between pancreatic cancer cells and stellate cells via activation of the metastasis suppressor NDRG1. Journal of Biological Chemistry 2022, 298 (3) , 101608.
    69. Viktor A. Timoshnikov, Olga Yu. Selyutina, Nikolay E. Polyakov, Victoria Didichenko, George J. Kontoghiorghes. Mechanistic Insights of Chelator Complexes with Essential Transition Metals: Antioxidant/Pro-Oxidant Activity and Applications in Medicine. International Journal of Molecular Sciences 2022, 23 (3) , 1247.
    70. Touba Eslaminejad, Yaghoub Pourshojaei, Mahmood Naghizadeh, Hoda Eslami, Mohammad Daneshpajouh, Abdolreza Hassanzadeh. Synthesis of some benzylidene thiosemicarbazide derivatives and evaluation of their cytotoxicity on U87, MCF-7, A549, 3T3 and HUVEC cell lines. Journal of the Serbian Chemical Society 2022, 87 (10) , 1125-1142.
    71. Tharushi P. Wijesinghe, Mahendiran Dharmasivam, Charles C. Dai, Des R. Richardson. Innovative therapies for neuroblastoma: The surprisingly potent role of iron chelation in up-regulating metastasis and tumor suppressors and down-regulating the key oncogene, N-myc. Pharmacological Research 2021, 173 , 105889.
    72. Jia Shao, Qiang Zhang, Jing Wei, Zhiguang Yuchi, Peng Cao, Shao-Qing Li, Shan Wang, Jing-Yuan Xu, Shuang Yang, Yi Zhang, Jin-Xia Wei, Jin-Lei Tian. Synthesis, crystal structures, anticancer activities and molecular docking studies of novel thiazolidinone Cu( ii ) and Fe( iii ) complexes targeting lysosomes: special emphasis on their binding to DNA/BSA. Dalton Transactions 2021, 50 (38) , 13387-13398.
    73. Burcu Saygıdeğer Demir, Ghodrat Mahmoudi, Aycan Sezan, Ezgi Derinöz, Eylem Nas, Yasemin Saygideger, Fedor I. Zubkov, Ennio Zangrando, Damir A. Safin. Evaluation of the antitumor activity of a series of the pincer-type metallocomplexes produced from isonicotinohydrazide derivative. Journal of Inorganic Biochemistry 2021, 223 , 111525.
    74. , Qianqian Fu. Di-2-pyridylketone 4, 4-dimethyl-3-thiosemicarbazone effectively induces human colorectal carcinoma cell apoptosis via mTOR pathway. Aging Pathobiology and Therapeutics 2021, 3 (3) , 56-62.
    75. Yu‐Shien Sung, Wangbin Wu, Megan A. Ewbank, Rachel D. Utterback, Michael T. Marty, Elisa Tomat. Albumin Conjugates of Thiosemicarbazone and Imidazole‐2‐thione Prochelators: Iron Coordination and Antiproliferative Activity. ChemMedChem 2021, 16 (18) , 2764-2768.
    76. Jason Chekmarev, Mahan Gholam Azad, Des R. Richardson. The Oncogenic Signaling Disruptor, NDRG1: Molecular and Cellular Mechanisms of Activity. Cells 2021, 10 (9) , 2382.
    77. Marcelo Melotti, Matheus S. S. Paqui, André L. Amorim, Carla P. de Paula, Marina C. Rocha, Iran Malavazi, Anderson Cunha, Francielli S. Santana, Ronny R. Ribeiro, Rogério A. Gariani, Samuel R. Mendes, Fernando R. Xavier. Polypyridyl iron( iii ) complexes containing long alkyl chains: synthesis, characterization, DFT calculations and biological activity. New Journal of Chemistry 2021, 45 (29) , 12902-12914.
    78. Maryam Hosseinkhah, Reza Ghasemian, Faezeh Shokrollahi, Samira Rezaei Mojdehi, Mahboubeh Jahani Sayyad Noveiri, Mohammad Hedayati, Marjan Rezaei, Ali Salehzadeh. Cytotoxic Potential of Nickel Oxide Nanoparticles Functionalized with Glutamic Acid and Conjugated with Thiosemicarbazide (NiO@Glu/TSC) Against Human Gastric Cancer Cells. Journal of Cluster Science 2021, 47
    79. Jia-Qi Li, Han Gao, Le Zhai, Le-Yun Sun, Cheng Chen, Jia-Zhu Chigan, Huan-Huan Ding, Ke-Wu Yang. Dipyridyl-substituted thiosemicarbazone as a potent broad-spectrum inhibitor of metallo-β-lactamases. Bioorganic & Medicinal Chemistry 2021, 38 , 116128.
    80. Erendra Manandhar, Ashley D. G. Johnson, William M. Watson, Shelby D. Dickerson, Gyan S. Sahukhal, Mohamed O. Elasri, Frank R. Fronczek, Peter J. Cragg, Karl J. Wallace. Detection of ferric ions in a gram-positive bacterial cell: Staphylococcus aureus. Journal of Coordination Chemistry 2021, 74 (1-3) , 380-401.
    81. 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.
    82. Hai-Yan Wang, Li Weng, Hong-Yan Yang, Xi Yang, Xiao-Ling Dong, Xiao-Mei Tan, Yan Wang. Heterometallic coordination polymers: Treatment activity on diabetic foot by reducing the excess inflammatory response in the plantar tissue. Journal of Chemical Research 2021, 45 (1-2) , 49-55.
    83. 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
    84. 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.
    85. 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.
    86. 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.
    87. 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.
    88. 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.
    89. 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.
    90. 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.
    91. 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.
    92. 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.
    93. 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.
    94. 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.
    95. 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.
    96. C.K. Holley, S. Majd. Examining the Anti-Tumor Activity of Dp44mT-Loaded Nanoparticles In Vitro. 2020, 5029-5032.
    97. 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.
    98. 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.
    99. 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.
    100. 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.
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