title: The synthesis and characterization of a series of cobalt(II) β-ketoaminato complexes and their cytotoxic activity towards human tumor cell lines.
abstract: A series of square planar cobalt(II) compounds bearing tetradentate β-ketoaminato ligands with variation in the number of -CF(3) ligand substituents has been prepared and structurally and spectroscopically characterized. The fluorinated β-ketoamine ligands were prepared utilizing a multistep reaction sequence employing a silylenol protecting group. An additional tetrahedral cobalt compound bearing two bidentate β-ketoaminato ligands was also prepared and characterized. Cytotoxic activity of the cobalt-containing complexes was evaluated using six human cell lines; including two different prostate cancer cell lines (PC-3 and VCaP), acute monocytic leukemia (THP-1), astrocytoma (U-373 MG), hepatocellular carcinoma (HepG2), and neuroblastoma (SH-SY5Y) cells. The cobalt compounds are more active than their corresponding ligands. The activity is cell type specific; the cobalt compounds exhibit strong activity against human prostate cancer and monocytic leukemia cells but weak or no activity against neuroblastoma, astrocytoma, and liver carcinoma cells. Activity generally increases with a greater number of -CF(3) substituents, and square planar complexes exhibit greater activity than the tetrahedral derivative. The mechanisms of activity against human PC-3 prostate cancer cells involve caspase-3 and two different mitogen-activated protein kinases. The addition of a thiol antioxidant reduced cytotoxicity, suggesting the possible involvement of reactive oxygen species. These cobalt complexes may represent a novel class of cytotoxic drugs selective towards certain types of tumors.
authors.affiliation: Department of Chemistry, University of British Columbia Okanagan, 3333 University Way, Kelowna, British Columbia, Canada, V1V 1V7.
authors.forename: Lydia
authors.initials: L
authors.lastname: Gurley
authors.forename: Natalia
authors.initials: N
authors.lastname: Beloukhina
authors.forename: Kalun
authors.initials: K
authors.lastname: Boudreau
authors.forename: Andis
authors.initials: A
authors.lastname: Klegeris
authors.forename: W Stephen
authors.initials: WS
authors.lastname: McNeil
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D003035:Cobalt / Q000737:chemistry*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008024:Ligands; D017382:Reactive Oxygen Species; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D017382:Reactive Oxygen Species; D003035:Cobalt; D053148:Caspase 3