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Cu(II) Propionyl-Thiazole Thiosemicarbazone Complexes: Crystal Structure, Inhibition of Human Topoisomerase IIα, and Activity against Breast Cancer Cells

DOI: 10.4236/ojmc.2018.82004, PP. 30-46

Keywords: Topoisomerase, Breast Cancer, Thiosemicarbazones

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Two new thiosemicarbazone ligands, 2-propionylthiazole ethylthiosemicarbazone (PTZ-ETSC), and 2-propionylthiazole tert-butylthiosemicarbazone (PTZ-tBTSC), along with their two copper(II) complexes, [Cu(PTZ-ETSC)Cl] and [Cu(PTZ-tBTSC)Cl], are reported here for the first time. Once characterized by NMR and MS, these mono-anionic tridentate ligands were reacted with Cu2+ to form the square planar metal complexes [Cu(PTZ-ETSC)Cl] and [Cu(PTZ-tBTSC)Cl]. The x-ray crystal structure of the [Cu(PTZ-tBTSC)Cl] complex shows that the complex adopts a square planar arrangement around the copper(II) ion, but forms a sulfur-bridged dimer in the solid state. Both of the copper complexes displayed strong inhibition of human topoisomerase IIα at activities between 2-4 μM for [Cu(PTZ-ETSC)Cl], and between 8-10 μM for the [Cu(PTZ-tBTSC)Cl] complex. The EC50 values for the MDA-MB-231 breast cancer cell line were 82.6 μM for (PTZ-ETSC), 17.9 μM for [Cu(PTZ- ETSC)Cl], 97.8 μM for (PTZ-tBTSC), and 1.41 μM for [Cu(PTZ-tBTSC)Cl]. The EC50 values for the MCF7 breast cancer cell lines were 9.36 μM for (PTZ-ETSC), 0.13 μM for [Cu(PTZ-ETSC)Cl], 0.333 μM for (PTZ-tBTSC), and 0.093 μM for [Cu(PTZ-tBTSC)Cl].


[1]  Beraldo, H. and Gambino, D. (2004) The Wide Pharmacological Versatility of Semicarbazones, Thiosemicarbazones and Their Metal Complexes. Mini-Rev. Medicinal Chemistry, 4, 31-39.
[2]  Brockman, R., Sidwell R., Arnett G. and Shaddix, S. (1970) Heterocyclic Thiosemicarbazones: Correlation between Structure, Inhibition of Ribonucleotide Reductase, and Inhibition of DNA Viruses. Experimental Biology and Medicine, 133, 609-614.
[3]  Bavin, E.M., Rees, R.J.W., Robson, J.M., Seiler, M., Seymour, D.E. and Suddaby, D. (1950) The Tuberculostatic Activity of Some Thiosemicarbazones. Journal of Pharmacy and Pharmacology, 2, 764-772.
[4]  Koch, O. and Stuttgen, G. (1950) Clinical and Experimental Studies on the Effects of Thiosemicarbazones. Naunyn-Schmiedebergs Archiv für experimentelle Pathologie und Pharmakologie, 210, 409-423.
[5]  Kune, G.A. (1964) Today’s Drugs: Methisazone. British Medical Journal, 2, 621.
[6]  Padhye, S. and Kauffman, G.B. (1985) Transition Metal Complexes of Semicarbazones and Thiosemicarbazones. Coordination Chemistry Reviews, 63, 127-160.
[7]  Casas, J.S., Garcia-Tasende, M.S. and Sordo, J. (2000) Main Group Metal Complexes of Semicarbazones and Thiosemicarbazones. A Structural Review. Coordination Chemistry Reviews, 209, 197-261.
[8]  Yu, Y., Kalinowski, D.S., Kovacevic, Z., Siafakas, A.R., Jansson, P.J., Stefani, C., Lovejoy, D.B., Sharpe, P.C., Bernhardt, P.V. and Richardson, D.R. (2009) Thiosemicarbazones from the Old to New: Iron Chelators That Are More than just Ribonucleotide Reductase Inhibitors. Journal of Medicinal Chemistry, 52, 5271-5294.
[9]  Matesanz, A. and Souza, P. (2009) α-N-Heterocyclic Thiosemicarbazone Derivatives as Potential Antitumor Agents: A Structure-Activity Relationship. Mini-Reviews in Medicinal Chemistry, 9, 1389-1396.
[10]  Moorthy, N., Cerquiera, N., Ramos, M. and Fernandez, P. (2013) Development of Ribonucleotide Reductase Inhibitor: A Review on Structure Activity Relationships. Mini-Reviews in Medicinal Chemistry, 13, 1-11.
[11]  Finch, R.A., Liu, M., Grill, S.P., Rose, W.C., Loomis, R., Vasquez, K.M., Cheng, Y.C. and Sartorelli, A.C. (2000) Triapine (3-Aminopyridine-2-Carboxalde- hyde-Thiosemicarbazone): A Potent Inhibitor of Ribonucleotide Reductase Activity with Broad Spectrum Antitumor Activity. Biochemical Pharmacology, 59, 983-991.
[12]  Knox, J.J., Hotte, S.J., Kollmannsberger, C., Winquist, E., Fisher, B. and Eisenhauer, E.A. (2007) 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). Investigational New Drugs, 25, 471-477.
[13]  Ma, B., Goh, B.C., Tan, E.H., Lam, K.C., Soo, R., Leong, S. S., et al. (2008) A Multicenter Phase II Trial of 3-Aminopyridine-2-Carboxaldehyde Thiosemicarbazone (3-AP, Triapine®) and Gemcitabine in Advanced Non-Small-Cell Lung Cancer with Pharmacokinetic Evaluation Using Peripheral Blood Mononuclear Cells. Investigational New Drugs, 26, 169-173.
[14]  West, D.X., Ives, J.S., Krejci, J., Salberg, M.M., Zumbahlen, T.L., Bain, G.A. and Toscano, R.A. (1995) Copper (II) Complexes of 2-Benzoylpyridine 4N-Substituted Thiosemicarbazones. Polyhedron, 14, 2189-2200.
[15]  Easmon, J., Puerstinger, G., Heinisch, G., Roth, T., Fiebig, H.H., Holzer, W., Jaeger, W., Jenny, M. and Hofmann, J. (2001) Synthesis, Cytotoxicity, and Antitumor Activity of Copper(II) and Iron(II) Complexes of 4N-Azabicyclo[3.2.2]Nonane Thiosemicarbazones Derived from Acyl Diazines. Journal of Medicinal Chemistry, 44, 2164-2171.
[16]  Shao, J., Zhou, B., Di Bilio, A.J., Zhu, L., Wang, T., Qi, C., Shih, J. and Yen, Y. (2006) A Ferrous-Triapine Complex Mediates Formation of Reactive Oxygen Species That Inactivate Human Ribonucleotide Reductase. Molecular Cancer Therapeutics, 5, 586-592.
[17]  Kalinowski, D.S. and Richardson, D.R. (2007) Future of Toxicology iron Chelators and Differing Modes of Action and Toxicity: The Changing Face of Iron Chelation Therapy. Chemical Research in Toxicology, 20, 715-720.
[18]  Jansson, P.J., Sharpe, P.C., Bernhardt, P.V. and Richardson, D.R. (2010) Novel Thiosemicarbazones of the ApT and DpT Series and Their Copper Complexes: Identification of Pronounced Redox Activity and Characterization of Their Antitumor Activity. Journal of Medicinal Chemistry, 53, 5759-5769.
[19]  Zeglis, B.M., Divilov, V. and Lewis, J.S. (2011) Role of Metalation in the Topoisomerase IIα Inhibition and Antiproliferation Activity of a Series of α-Heterocyclic- N4-Substituted Thiosemicarbazones and Their Cu(II) Complexes. Journal of Medicinal Chemistry, 54, 2391-2398.
[20]  Yalowich, J.C., et al. (2012) The Anticancer Thiosemicarbazones Dp44mT and Triapine Lack Inhibitory Effects as Catalytic Inhibitors or Poisons of DNA Topoisomerase IIα. Biochemical Pharmacology, 84, 52-58.
[21]  Wilson, J.T., Jiang, X., McGill, B.C., Lisic, E.C. and Deweese, J.E. (2016) Examination of the Impact of Copper(II) α-(N)-Heterocyclic Thiosemicarbazone Complexes on DNA Topoisomerase IIα. Chemical Research in Toxicology, 29, 649-658.
[22]  Conner, J.D., Medawala, W., Stephens, M.T., Morris, W.H., Deweese, J.E., Kent, P.L., Rice, J.J., Jiang, X. and Lisic, E.C. (2016) Cu(II) Benzoylpyridine Thiosemicarbazone Complexes: Inhibition of Human Topoisomerase IIα and Activity against Breast Cancer Cells. Open Journal of Inorganic Chemistry, 6, 146.
[23]  Regal, K.M., Mercer, S.L. and Deweese, J.E. (2014) HU-331 Is a Catalytic Inhibitor of Topoisomerase IIα. Chemical Research in Toxicology, 24, 2044-2051.
[24]  Sheldrick, G.M. (2008) A Short History of SHELX. Acta Crystallographica Section A, 64, 112-122.
[25]  Carroll, W.R., Gardner, D.M., Melton, E.R., Murphy, S.T., Buckner, A.K., Fulmer, M.S., Qualls, W.G. and Lisic, E.C. (2018) 1H, 13C, and 15N NMR Conformational Characterization of a Series of 2-Acetylthiazolethiosemicarbazone Compounds. Journal of Molecular Structure, 1157, 8-13.
[26]  Qi, J., Liang, S., Gou, Y., Zhang Z., Zhou, Z., Yang, F. and Liang, H. (2015) Synthesis of Four Binuclear Copper(II) Complexes: Structure, Anticancer Properties and Anticancer Mechanism. European Journal of Medicinal Chemistry, 96, 360-368.
[27]  Gil-Garcia, R., Gomez-Saiz, P., Diez-Gomez, V., Madariaga, G., Insausti, M., Lezama, L., Cuevas, J.V. and Garcia-Tojal, J. (2014) Thiosemicarbazonecopper(II) Compounds with Hal-ide/Hexafluorosilicate Anions: Structure, Water Clusters, Non-Covalent Interactions and Magnetism. Polyhedron, 81, 675-686.
[28]  Naskar, S., Naskar, S., Mayer-Figge, H., Sheldrick, W.S., Corbella, M., Tercero, J. and Chattopadhyay, S.K. (2012) Study of Copper(II) Complexes of Two Diacetyl Monooxime Thiosemicarbazones: X-Ray Crystal Structure and Magneto-Structural Correlation of [Cu(dmoTSCH)Cl]2xH2O (dmoTSCH = Monoanion of Diacetyl Monooxime Thiosemicarbazone). Polyhedron, 97, 157-166.
[29]  Garcia, B., Garcia-Tojal, J., Ruiz, R., Gil-Garcia, R., Ibeas, S., Donnadieu, B. and Leal, J.M. (2008) Interaction of the DNA Bases and Their Mononucleotides with Pyridine-2-Carbaldehyde Thiosemicarbazone Copper(II) Complexes. Structure of the Cytosine Derivative. Journal of Inorganic Biochemistry, 102, 1892-1900.
[30]  Ilies, Diana-C., Shova, S., Radescu, V., Pahontu, E. and Rosu, T. (2015) Synthesis, Characterization, Crystal Structure and Antioxidant Activity of Ni(II) and Cu(II) Complexes with 2-Formilpyridine N(4)-Phenylthiosemicarbazone. Polyhedron, 97, 157-166.
[31]  Muralisankar, M., Sujith, S., Bhuvanesh, N.S.P. and Sreekanth, A. (2016) Synthesis and Crystal Structure of New Monometallic and Bimetallic Copper(II) Complexes with N-Substituted Isatin Thiosemicarbazone Ligands: Effects of the Complexes on DNA/Protein-Binding Property, DNA Cleavage Study and in Vitro Anticancer Activity. Polyhedron, 118, 103-117.
[32]  Sreekanth, A. and Prathapachandra Karup, M.R. (2003) Structural and Spectral Studies on Four Coordinate Copper(II) Complexes of 2-Benzoylpyridine N(4), N(4)-(butane-1,4-diyl) Thiosemicarbazone. Polyhedron, 22, 3321-3332.


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