2-acetylpyridine thiosemicarbazones are potent Iron chelators and antiproliferative agents

redox activity, iron complexation and characterization of their antitumor activity

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

*Corresponding author for this work

Research output: Contribution to journalArticle

151 Citations (Scopus)

Abstract

Through systematic structure-activity studies of the 2-benzoylpyridine thiosemicarbazone (HBpT), 2-(3-nitrobenzoyl)pyridine thiosemicarbazone (HNBpT) and dipyridylketone thiosemicarbazone (HDpT) series of iron (Fe) chelators, we identified structural features necessary to form Fe complexes with potent anticancer activity (J. Med. Chem. 2007, 50, 3716-3729). In this investigation, we generated the related 2-acetylpyridine thiosemicarbazone (HApT) analogues to examine the influence of the methyl group at the imine carbon. Four of the six HApT chelators had potent antitumor activity (IC(50): 0.001-0.002 mu M) and Fe chelation efficacy that was similar to the most effective HBpT and HDpT ligands. The HApT Fe complexes had the lowest Fe(III/II) redox potentials of any thiosemicarbazone series we have generated. This property, in combination with their ability to effectively chelate cellular Fe, make the HApT series one of the most potent antiproliferative agents developed by our group.

Original languageEnglish
Pages (from-to)1459-1470
Number of pages12
JournalJournal of Medicinal Chemistry
Volume52
Issue number5
DOIs
Publication statusPublished - 12 Mar 2009
Externally publishedYes

Keywords

  • PYRIDOXAL ISONICOTINOYL HYDRAZONE
  • RIBONUCLEOTIDE REDUCTASE INHIBITOR
  • 3-AMINOPYRIDINE-2-CARBOXALDEHYDE THIOSEMICARBAZONE
  • ANTIMICROBIAL ACTIVITIES
  • SEMICARBAZONE LIGANDS
  • IRON(III) COMPLEXES
  • MOLECULAR-STRUCTURE
  • BIOLOGICAL-ACTIVITY
  • ZINC(II) COMPLEXES
  • CRYSTAL-STRUCTURES

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