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

J Med Chem. 2012 Aug 23;55(16):7230-44. doi: 10.1021/jm300768u. Epub 2012 Aug 3.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Coordination Complexes / chemical synthesis*
  • Coordination Complexes / chemistry
  • Coordination Complexes / pharmacology
  • Copper*
  • Crystallography, X-Ray
  • Dimerization
  • Drug Screening Assays, Antitumor
  • Drug Synergism
  • Humans
  • Injections, Intravenous
  • Ketones / chemical synthesis*
  • Ketones / chemistry
  • Ketones / pharmacology
  • Lung Neoplasms / drug therapy*
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Oxidation-Reduction
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Pyridines / pharmacology
  • Structure-Activity Relationship
  • Thiosemicarbazones / chemical synthesis*
  • Thiosemicarbazones / chemistry
  • Thiosemicarbazones / pharmacology
  • Transferrin / metabolism
  • Transplantation, Heterologous


  • Antineoplastic Agents
  • Coordination Complexes
  • Ketones
  • Pyridines
  • Thiosemicarbazones
  • Transferrin
  • Copper