Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 55, Issue 16, Pages 7230-7244Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm300768u
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Funding
- National Health and Medical Research Council (NHMRC) Australia [632778]
- NHMRC Senior Principal Research Fellowship [571123]
- Cancer Institute New South Wales Early Career Development Fellowship [07/ECF/1-19, 10/ECF/2-15, 08/ECF/1-30]
- Cancer Institute Research Innovation Grant [10/RFG/2-50]
- Australian Research Council Discovery Grant [DP1096029]
- King Abdul Aziz University Scholarship
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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 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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