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Novel Second-Generation Di-2-Pyridylketone Thiosemicarbazones Show Synergism with Standard Chemotherapeutics and Demonstrate Potent Activity against Lung Cancer Xenografts after Oral and Intravenous Administration in Vivo

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Iron Metabolism and Chelation Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia
School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland 4072, Australia
*Phone: +61-2-9036-6548. Fax: +61-2-9036-6549. E-mail: [email protected]
Cite this: J. Med. Chem. 2012, 55, 16, 7230–7244
Publication Date (Web):August 3, 2012
https://doi.org/10.1021/jm300768u
Copyright © 2012 American Chemical Society

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    Abstract

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    We developed a series of second-generation di-2-pyridyl ketone thiosemicarbazone (DpT) and 2-benzoylpyridine thiosemicarbazone (BpT) ligands to improve the efficacy and safety profile of these potential antitumor agents. Two novel DpT analogues, Dp4e4mT and DpC, exhibited pronounced and selective activity against human lung cancer xenografts in vivo via the intravenous and oral routes. Importantly, these analogues did not induce the cardiotoxicity observed at high nonoptimal doses of the first-generation DpT analogue, Dp44mT. The Cu(II) complexes of these ligands exhibited potent antiproliferative activity having redox potentials in a range accessible to biological reductants. The activity of the copper complexes of Dp4e4mT and DpC against lung cancer cells was synergistic in combination with gemcitabine or cisplatin. It was demonstrated by EPR spectroscopy that dimeric copper compounds of the type [CuLCl]2, identified crystallographically, dissociate in solution to give monomeric 1:1 Cu:ligand complexes. These monomers represent the biologically active form of the complex.

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    Body and organ weights, hematological indices from in vivo tumor xenograft experiments, experimental and simulated EPR spectra, and cyclic voltammetry of Cu complexes. This material is available free of charge via the Internet at http://pubs.acs.org.

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    68. 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
    69. Raquel Alcaraz, Pilar Muñiz, Mónica Cavia, Óscar Palacios, Katia G. Samper, Rubén Gil-García, Alondra Jiménez-Pérez, Javier García-Tojal, Carlos García-Girón. Thiosemicarbazone-metal complexes exhibiting cytotoxicity in colon cancer cell lines through oxidative stress. Journal of Inorganic Biochemistry 2020, 206 , 110993. https://doi.org/10.1016/j.jinorgbio.2020.110993
    70. Sundus N. Maqbool, Syer C. Lim, Kyung Chan Park, Rumeza Hanif, Des R. Richardson, Patric J. Jansson, Zaklina Kovacevic. Overcoming tamoxifen resistance in oestrogen receptor‐positive breast cancer using the novel thiosemicarbazone anti‐cancer agent, DpC. British Journal of Pharmacology 2020, 177 (10) , 2365-2380. https://doi.org/10.1111/bph.14985
    71. Rikki A. M. Brown, Kirsty L. Richardson, Tasnuva D. Kabir, Debbie Trinder, Ruth Ganss, Peter J. Leedman. Altered Iron Metabolism and Impact in Cancer Biology, Metastasis, and Immunology. Frontiers in Oncology 2020, 10 https://doi.org/10.3389/fonc.2020.00476
    72. Alireza Habibi, Seyed Ataollah Sadat Shandiz, Ali salehzadeh, Zeinab Moradi-Shoeili. Novel pyridinecarboxaldehyde thiosemicarbazone conjugated magnetite nanoparticulates (MNPs) promote apoptosis in human lung cancer A549 cells. JBIC Journal of Biological Inorganic Chemistry 2020, 25 (1) , 13-22. https://doi.org/10.1007/s00775-019-01728-4
    73. 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
    74. Tishauna L.C. Green, Peter N. Nelson, Mark A.W. Lawrence. Spectroscopic, optical sensing and RedOx behaviour of 1, 5-diphenylcarbazone. Journal of Molecular Structure 2019, 1195 , 426-434. https://doi.org/10.1016/j.molstruc.2019.06.011
    75. Mark A.W. Lawrence, Shannen C. Lorraine, Kerrie-Ann Wilson, Kirk Wilson. Review: Voltammetric properties and applications of hydrazones and azo moieties. Polyhedron 2019, 173 , 114111. https://doi.org/10.1016/j.poly.2019.114111
    76. 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
    77. 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
    78. 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
    79. 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
    80. Petra Reimerová, Ján Stariat, Hana Bavlovič Piskáčková, Hana Jansová, Jaroslav Roh, Danuta S. Kalinowski, Miloslav Macháček, Tomáš Šimůnek, Des R. Richardson, Petra Štěrbová-Kovaříková. Novel SPME fibers based on a plastic support for determination of plasma protein binding of thiosemicarbazone metal chelators: a case example of DpC, an anti-cancer drug that entered clinical trials. Analytical and Bioanalytical Chemistry 2019, 411 (11) , 2383-2394. https://doi.org/10.1007/s00216-019-01681-w
    81. 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
    82. Hana Jansová, Tomáś Šimůnek. Cardioprotective Potential of Iron Chelators and Prochelators. Current Medicinal Chemistry 2019, 26 (2) , 288-301. https://doi.org/10.2174/0929867324666170920155439
    83. 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
    84. 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
    85. Rayan S. Moussa, Kyung Chan Park, Zaklina Kovacevic, Des R. Richardson. Ironing out the role of the cyclin-dependent kinase inhibitor, p21 in cancer: Novel iron chelating agents to target p21 expression and activity. Free Radical Biology and Medicine 2019, 133 , 276-294. https://doi.org/10.1016/j.freeradbiomed.2018.03.027
    86. 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
    87. Wanbao Cao, Jinxu Qi, Kun Qian, Liang Tian, Zhen Cheng, Yihong Wang. Structure−activity relationships of 2‑quinolinecarboxaldehyde thiosemicarbazone gallium(III) complexes with potent and selective anticancer activity. Journal of Inorganic Biochemistry 2019, 191 , 174-182. https://doi.org/10.1016/j.jinorgbio.2018.11.017
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