title: Iron chelators of the dipyridylketone thiosemicarbazone class: precomplexation and transmetalation effects on anticancer activity.
abstract: We previously reported a series of di-2-pyridylketone thiosemicarbazone (HDpT) chelators that showed marked and selective antitumor activity (Whitnall, M.; et al. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 14901-14906). To further understand their biological efficacy, we report the characterization and activity of their Mn(II), Co(III), Ni(II), Cu(II), and Zn(II) complexes. The X-ray crystal structures of four divalent (Mn, Ni, Cu, and Zn) and one trivalent (Fe) complexes are reported. Electrochemistry shows the Fe(III/II) and Cu(II/I) potentials of the complexes may be redox-active within cells. Stability constants were also determined for the Mn(II), Ni(II), Cu(II), and Zn(II) complexes. All divalent complexes underwent transmetalation upon encountering Fe(II), to form low spin ferrous complexes. Importantly, the divalent Mn(II), Ni(II), Cu(II), and Zn(II) complexes of the HDpT analogues are equally active in preventing proliferation as their ligands, suggesting the complexes act as lipophilic vehicles facilitating intracellular delivery of the free ligand upon metal dissociation.
authors.affiliation: Centre for Metals in Biology, School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Qld 4072, Australia. p.bernhardt@uq.edu.au
authors.forename: Paul V
authors.initials: PV
authors.lastname: Bernhardt
authors.forename: Philip C
authors.initials: PC
authors.lastname: Sharpe
authors.forename: Mohammad
authors.initials: M
authors.lastname: Islam
authors.forename: David B
authors.initials: DB
authors.lastname: Lovejoy
authors.forename: Danuta S
authors.initials: DS
authors.lastname: Kalinowski
authors.forename: Des R
authors.initials: DR
authors.lastname: Richardson
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004563:Electrochemistry; D018922:HL-60 Cells; D006801:Humans; D007502:Iron Chelating Agents / Q000737:chemistry* / Q000494:pharmacology; D007659:Ketones / Q000737:chemistry*; D008670:Metals / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D013056:Spectrophotometry, Ultraviolet; D013882:Thiosemicarbazones / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D007502:Iron Chelating Agents; D007659:Ketones; D008670:Metals; D013882:Thiosemicarbazones