title: Coordination of hydroxyquinolines to a ruthenium bis-dimethyl-phenanthroline scaffold radically improves potency for potential as antineoplastic agents.
abstract: A series of ruthenium coordination complexes containing hydroxyquinoline ligands were synthesized that exhibited radically improved potencies up to 86-fold greater than clioquinol, a known cytotoxic compound. The complexes were also >100-fold more potent than clioquinol in a tumor spheroid model, with values similar to currently used chemotherapeutics for the treatment of solid tumors. Cytotoxicity occurs through rapid processes that induce apoptosis but appear to be mediated by cell-cycle independent mechanisms. The ruthenium complexes do not inhibit the proteasome at concentrations relevant for cell death, and contrary to previous reports, clioquinol and other hydroxyquinoline compounds do not act as direct proteasome inhibitors to induce cell death.
authors.affiliation: Department of Chemistry, University of Kentucky , 505 Rose Street, Lexington, Kentucky 40506, United States.
authors.forename: David K
authors.initials: DK
authors.lastname: Heidary
authors.forename: Brock S
authors.initials: BS
authors.lastname: Howerton
authors.forename: Edith C
authors.initials: EC
authors.lastname: Glazer
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D007464:Clioquinol / Q000494:pharmacology; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000494:pharmacology*; D003300:Copper / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D006912:Hydroxyquinolines / Q000138:chemical synthesis / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D061988:Proteasome Inhibitors / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis / Q000494:pharmacology*; D012428:Ruthenium / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D006912:Hydroxyquinolines; D061988:Proteasome Inhibitors; D011804:Quinolines; D003300:Copper; D007464:Clioquinol; D012428:Ruthenium; C029892:cupric chloride