Iron chelators of the dipyridylketone thiosemicarbazone class

precomplexation and transmetalation effects on anticancer activity

Paul V. Bemhardt*, Philip C. Sharpe, Mohammad Islam, David B. Lovejoy, Danuta S. Kalinowski, Des R. Richardson

*Corresponding author for this work

Research output: Contribution to journalArticle

127 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)407-415
Number of pages9
JournalJournal of Medicinal Chemistry
Volume52
Issue number2
DOIs
Publication statusPublished - 22 Jan 2009
Externally publishedYes

Keywords

  • PYRIDOXAL ISONICOTINOYL HYDRAZONE
  • BINUCLEAR COPPER(II) COMPLEXES
  • SELECTIVE ANTITUMOR-ACTIVITY
  • COORDINATION CHEMISTRY
  • ANTIPROLIFERATIVE ACTIVITY
  • SPECTRAL INVESTIGATIONS
  • OVERLOAD DISORDERS
  • IRON(III) COMPLEX
  • CRYSTAL-STRUCTURE
  • HEME-SYNTHESIS

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