Design, synthesis, and characterization of novel iron chelators: structure-activity relationships of the 2-benzoylpyridine thiosemicarbazone series and their 3-nitrobenzoyl analogues as potent antitumor agents

Danuta S. Kalinowski, Yu Yu, Philip C. Sharpe, Mohammad Islam, Yi-Tyng Liao, David B. Lovejoy, Naresh Kumar, Paul V. Bernhardt*, Des R. Richardson

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

188 Citations (Scopus)

Abstract

Previously, we demonstrated that the potent antiproliferative activity of the di-2-pyridylketone thiosemicarbazone (DpT) series of Fe chelators was due to their ability to induce Fe depletion and form redox-active Fe complexes (Richardson, D. R.; et al. J. Med. Chem. 2006, 49, 6510-6521). We now examine the role of aromatic substituents on the antiproliferative and redox activity of novel DpT analogues, namely, the 2-benzoylpyridine thiosemicarbazone (BpT) and 2-(3-nitrobenzoyl)pyridine thiosemicarbazone (NBpT) series. Both series exhibited selective antiproliferative effects, with the majority having greater antineoplastic activity than their DpT homologues. This makes the BpT chelators the most active anticancer agents developed within our laboratory. The BpT series Fe complexes exhibit lower redox potentials than their corresponding DpT and NBpT complexes, highlighting their enhanced redox activity. The increased ability of BpT-Fe complexes to catalyze ascorbate oxidation and benzoate hydroxylation, relative to their DpT and NBpT analogues, suggested that redox cycling plays an important role in their antiproliferative activity.

Original languageEnglish
Pages (from-to)3716-3729
Number of pages14
JournalJournal of Medicinal Chemistry
Volume50
Issue number15
DOIs
Publication statusPublished - 26 Jul 2007
Externally publishedYes

Keywords

  • PYRIDOXAL ISONICOTINOYL HYDRAZONE
  • EFFECTIVE ANTIPROLIFERATIVE AGENTS
  • COPPER(II) COMPLEXES
  • OVERLOAD DISEASE
  • REDOX ACTIVITY
  • SPECTRAL CHARACTERIZATION
  • RIBONUCLEOTIDE REDUCTASE
  • CYTOTOXIC ACTIVITY
  • CRYSTAL-STRUCTURE
  • METAL CHELATOR

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