title: 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.
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.
authors.affiliation: Iron Metabolism and Chelation Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: David B
authors.initials: DB
authors.lastname: Lovejoy
authors.forename: Danae M
authors.initials: DM
authors.lastname: Sharp
authors.forename: Nicole
authors.initials: N
authors.lastname: Seebacher
authors.forename: Peyman
authors.initials: P
authors.lastname: Obeidy
authors.forename: Thomas
authors.initials: T
authors.lastname: Prichard
authors.forename: Christian
authors.initials: C
authors.lastname: Stefani
authors.forename: Maram T
authors.initials: MT
authors.lastname: Basha
authors.forename: Philip C
authors.initials: PC
authors.lastname: Sharpe
authors.forename: Patric J
authors.initials: PJ
authors.lastname: Jansson
authors.forename: Danuta S
authors.initials: DS
authors.lastname: Kalinowski
authors.forename: Paul V
authors.initials: PV
authors.lastname: Bernhardt
authors.forename: Des R
authors.initials: DR
authors.lastname: Richardson
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003300:Copper; D018360:Crystallography, X-Ray; D019281:Dimerization; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D007275:Injections, Intravenous; D007659:Ketones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010084:Oxidation-Reduction; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014168:Transferrin / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D007659:Ketones; D011725:Pyridines; D013882:Thiosemicarbazones; D014168:Transferrin; D003300:Copper