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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
Copyright © 2012 American Chemical Society

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    Abstract Image

    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

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