title: Halogenated 2'-benzoylpyridine thiosemicarbazone (XBpT) chelators with potent and selective anti-neoplastic activity: relationship to intracellular redox activity.
abstract: Iron chelators of the 2'-benzoylpyridine thiosemicarbazone (BpT) class show substantial potential as anticancer agents. To explore structure-activity relationships, new BpT analogues were designed that incorporated halogen substituents on the noncoordinating phenyl group (XBpTs). These XBpT ligands exhibited potent antiproliferative activity with some analogues exceeding that of the parent BpT compound. Importantly, there was an appreciable therapeutic index in vitro, as mortal cells were significantly less affected by these chelators relative to neoplastic cells. The addition of a halogen led to a halogen-specific increase in the redox potential of XBpT-Fe complexes. Probing for chelator-induced intracellular reactive oxygen species (ROS) with the fluorescent probe, 2',7'-dichlorofluorescein, revealed a 1.5-4.7-fold increase in fluorescence upon incorporation of Cl, Br, or I to the parent analogues. Furthermore, an important structure-activity relationship was deduced where the addition of halogens led to a positive correlation between intracellular ROS generation and antiproliferative activity in the more hydrophilic BpT parent compounds.
authors.affiliation: Iron Metabolism and Chelation Program, Department of Pathology, University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Christian
authors.initials: C
authors.lastname: Stefani
authors.forename: Gaya
authors.initials: G
authors.lastname: Punnia-Moorthy
authors.forename: David B
authors.initials: DB
authors.lastname: Lovejoy
authors.forename: Patric J
authors.initials: PJ
authors.lastname: Jansson
authors.forename: Danuta S
authors.initials: DS
authors.lastname: Kalinowski
authors.forename: Philip C
authors.initials: PC
authors.lastname: Sharpe
authors.forename: Paul V
authors.initials: PV
authors.lastname: Bernhardt
authors.forename: Des R
authors.initials: DR
authors.lastname: Richardson
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001205:Ascorbic Acid / Q000737:chemistry; D002460:Cell Line; 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; D004563:Electrochemistry; D005452:Fluoresceins; D005456:Fluorescent Dyes; D005470:Fluorometry; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007502:Iron Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D005452:Fluoresceins; D005456:Fluorescent Dyes; D007502:Iron Chelating Agents; D011725:Pyridines; D017382:Reactive Oxygen Species; D013882:Thiosemicarbazones; C037631:2',7'-dichlorofluorescein; D001205:Ascorbic Acid