title: Dipyridyl thiosemicarbazone chelators with potent and selective antitumor activity form iron complexes with redox activity.
abstract: There has been much interest in the development of iron (Fe) chelators for the treatment of cancer. We developed a series of di-2-pyridyl ketone thiosemicarbazone (HDpT) ligands which show marked and selective antitumor activity in vitro and in vivo. In this study, we assessed chemical and biological properties of these ligands and their Fe complexes in order to understand their marked activity. This included examination of their solution chemistry, electrochemistry, ability to mediate redox reactions, and antiproliferative activity against tumor cells. The higher antiproliferative efficacy of the HDpT series of chelators relative to the related di-2-pyridyl ketone isonicotinoyl hydrazone (HPKIH) analogues can be ascribed, in part, to the redox potentials of their Fe complexes which lead to the generation of reactive oxygen species. The most effective HDpT ligands as antiproliferative agents possess considerable lipophilicity and were shown to be charge neutral at physiological pH, allowing access to intracellular Fe pools.
authors.affiliation: Iron Metabolism and Chelation Program, Department of Pathology, University of Sydney, Sydney, New South Wales 2006, Australia. d.richardson@uq.edu.au
authors.forename: Des R
authors.initials: DR
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: Dakshita
authors.initials: D
authors.lastname: Senaratne
authors.forename: Danuta S
authors.initials: DS
authors.lastname: Kalinowski
authors.forename: Mohammad
authors.initials: M
authors.lastname: Islam
authors.forename: Paul V
authors.initials: PV
authors.lastname: Bernhardt
mesh_terms: D000970:Antineoplastic Agents; D001205:Ascorbic Acid / Q000737:chemistry; D001565:Benzoates / Q000737:chemistry; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D018360:Crystallography, X-Ray; D004247:DNA / Q000235:genetics; D004563:Electrochemistry; D006801:Humans; D006900:Hydroxylation; D007501:Iron / Q000737:chemistry*; D007502:Iron Chelating Agents / Q000737:chemistry* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010084:Oxidation-Reduction; D010957:Plasmids / Q000235:genetics; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001565:Benzoates; D007502:Iron Chelating Agents; D011725:Pyridines; D013882:Thiosemicarbazones; D004247:DNA; D007501:Iron; D001205:Ascorbic Acid