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

David B. Lovejoy, Danae M. Sharp, Nicole Seebacher, Peyrnan Obeidy, Thomas Prichard, Christian Stefani, Maram T. Basha, Philip C. Sharpe, Patric J. Jansson, Danuta S. Kalinowski, Paul V. Bernhardt, Des R. Richardson*

*Corresponding author for this work

Research output: Contribution to journalArticle

119 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)7230-7244
Number of pages15
JournalJournal of Medicinal Chemistry
Volume55
Issue number16
DOIs
Publication statusPublished - 23 Aug 2012
Externally publishedYes

Keywords

  • SELECTIVE ANTITUMOR-ACTIVITY
  • EFFECTIVE ANTIPROLIFERATIVE AGENTS
  • ATOMIC PHYSICOCHEMICAL PARAMETERS
  • ISONICOTINOYL HYDRAZONE CLASS
  • IRON CHELATORS
  • REDOX ACTIVITY
  • DRUG-COMBINATION
  • SCHIFF-BASE
  • RIBONUCLEOTIDE REDUCTASE
  • QUANTITATIVE STRUCTURE

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