Halogenated 2 '-benzoylpyridine thiosemicarbazone (xbpt) chelators with potent and selective anti-neoplastic activity

relationship to intracellular redox activity

Christian Stefani, Gaya Punnia-Moorthy, David B. Lovejoy, Patric J. Jansson, Danuta S. Kalinowski, Philip C. Sharpe, Paul V. Bernhardt, Des R. Richardson*

*Corresponding author for this work

Research output: Contribution to journalArticle

39 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)6936-6948
Number of pages13
JournalJournal of Medicinal Chemistry
Volume54
Issue number19
DOIs
Publication statusPublished - 13 Oct 2011
Externally publishedYes

Keywords

  • PYRIDOXAL ISONICOTINOYL HYDRAZONE
  • EFFECTIVE ANTIPROLIFERATIVE AGENTS
  • IRON OVERLOAD DISEASE
  • ANTITUMOR-ACTIVITY
  • RIBONUCLEOTIDE REDUCTASE
  • METAL CHELATOR
  • CELL-CYCLE
  • PHASE-II
  • IN-VITRO
  • ANALOGS

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