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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.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2012 Aug 23; Vol. 55 (16), pp. 7230-44. Date of Electronic Publication: 2012 Aug 03. - Publication Year :
- 2012
-
Abstract
- 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.
- Subjects :
- Administration, Oral
Animals
Antineoplastic Agents chemistry
Antineoplastic Agents pharmacology
Cell Line, Tumor
Coordination Complexes chemistry
Coordination Complexes pharmacology
Crystallography, X-Ray
Dimerization
Drug Screening Assays, Antitumor
Drug Synergism
Humans
Injections, Intravenous
Ketones chemistry
Ketones pharmacology
Mice
Mice, Nude
Neoplasm Transplantation
Oxidation-Reduction
Pyridines chemistry
Pyridines pharmacology
Structure-Activity Relationship
Thiosemicarbazones chemistry
Thiosemicarbazones pharmacology
Transferrin metabolism
Transplantation, Heterologous
Antineoplastic Agents chemical synthesis
Coordination Complexes chemical synthesis
Copper
Ketones chemical synthesis
Lung Neoplasms drug therapy
Pyridines chemical synthesis
Thiosemicarbazones chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 55
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 22861499
- Full Text :
- https://doi.org/10.1021/jm300768u