title: 2-Acetylpyridine thiosemicarbazones are potent iron chelators and antiproliferative agents: redox activity, iron complexation and characterization of their antitumor activity.
abstract: Through systematic structure-activity studies of the 2-benzoylpyridine thiosemicarbazone (HBpT), 2-(3-nitrobenzoyl)pyridine thiosemicarbazone (HNBpT) and dipyridylketone thiosemicarbazone (HDpT) series of iron (Fe) chelators, we identified structural features necessary to form Fe complexes with potent anticancer activity (J. Med. Chem. 2007, 50, 3716-3729). In this investigation, we generated the related 2-acetylpyridine thiosemicarbazone (HApT) analogues to examine the influence of the methyl group at the imine carbon. Four of the six HApT chelators had potent antitumor activity (IC(50): 0.001-0.002 microM) and Fe chelation efficacy that was similar to the most effective HBpT and HDpT ligands. The HApT Fe complexes had the lowest Fe(III/II) redox potentials of any thiosemicarbazone series we have generated. This property, in combination with their ability to effectively chelate cellular Fe, make the HApT series one of the most potent antiproliferative agents developed by our group.
authors.affiliation: Department of Pathology, University of Sydney, Sydney, New South Wales, Australia. d.richardson@med.usyd.edu.au
authors.forename: Des R
authors.initials: DR
authors.lastname: Richardson
authors.forename: Danuta S
authors.initials: DS
authors.lastname: Kalinowski
authors.forename: Vera
authors.initials: V
authors.lastname: Richardson
authors.forename: Philip C
authors.initials: PC
authors.lastname: Sharpe
authors.forename: David B
authors.initials: DB
authors.lastname: Lovejoy
authors.forename: Mohammad
authors.initials: M
authors.lastname: Islam
authors.forename: Paul V
authors.initials: PV
authors.lastname: Bernhardt
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001205:Ascorbic Acid / Q000737:chemistry; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D055664:Electrochemical Techniques; D006801:Humans; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010084:Oxidation-Reduction; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014168:Transferrin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D007502:Iron Chelating Agents; D011725:Pyridines; D013882:Thiosemicarbazones; D014168:Transferrin; D007501:Iron; D001205:Ascorbic Acid