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Novel Thiosemicarbazones of the ApT and DpT Series and Their Copper Complexes: Identification of Pronounced Redox Activity and Characterization of Their Antitumor Activity

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Department of Pathology and Bosch Institute, University of Sydney, Sydney, NSW 2006, Australia
Centre for Metals in Biology, School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Qld 4072, Australia
*To whom correspondence should be addressed. For P.V.B. (chemistry): phone, +61-7-3365-4266; fax, +61-7-3365-4299; e-mail, [email protected]. For D.R.R. (biology and chemistry): phone, +61-2-9036-6548; fax, +61-2-9036-6549; e-mail, [email protected]
§P.V.B. and D.R.R. contributed equally as senior authors.
Cite this: J. Med. Chem. 2010, 53, 15, 5759–5769
Publication Date (Web):July 2, 2010
https://doi.org/10.1021/jm100561b
Copyright © 2010 American Chemical Society

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    Abstract

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    The novel chelators 2-acetylpyridine-4,4-dimethyl-3-thiosemicarbazone (HAp44mT) and di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (HDp44mT) have been examined to elucidate the structure−activity relationships necessary to form copper (Cu) complexes with pronounced antitumor activity. Electrochemical studies demonstrated that the Cu complexes of these ligands had lower redox potentials than their iron complexes. Moreover, the Cu complexes where the ligand/metal ratio was 1:1 rather than 2:1 had significantly higher intracellular oxidative properties and antitumor efficacy. Interestingly, the 2:1 complex was shown to dissociate to give significant amounts of the 1:1 complex that could be the major cytotoxic effector. Both types of Cu complex showed significantly more antiproliferative activity than the ligand alone. We also demonstrate the importance of the inductive effects of substituents on the carbonyl group of the parent ketone, which influence the CuII/I redox potentials because of their proximity to the metal center. The structure−activity relationships described are important for the design of potent thiosemicarbazone Cu complexes.

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    Simulated and experimental EPR spectra including spin Hamiltonian parameters. This material is available free of charge via the Internet at http://pubs.acs.org.

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