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

doi:10.1021/jm801585u

2-Acetylpyridine thiosemicarbazones are potent iron chelators and antiproliferative agents: redox activity, iron complexation and characterization of their antitumor activity

J Med Chem. 2009 Mar 12;52(5):1459-70. doi: 10.1021/jm801585u.

Authors

Des R Richardson¹, Danuta S Kalinowski, Vera Richardson, Philip C Sharpe, David B Lovejoy, Mohammad Islam, Paul V Bernhardt

Affiliation

¹ Department of Pathology, University of Sydney, Sydney, New South Wales, Australia. d.richardson@med.usyd.edu.au

PMID: 19216562
DOI: 10.1021/jm801585u

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 microM) 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Ascorbic Acid / chemistry
Cell Line, Tumor
Cell Proliferation / drug effects
Coordination Complexes / chemical synthesis*
Coordination Complexes / chemistry
Coordination Complexes / pharmacology
Crystallography, X-Ray
Drug Screening Assays, Antitumor
Electrochemical Techniques
Humans
Iron / metabolism
Iron Chelating Agents / chemical synthesis*
Iron Chelating Agents / chemistry
Iron Chelating Agents / pharmacology
Oxidation-Reduction
Pyridines / chemical synthesis*
Pyridines / chemistry
Pyridines / pharmacology
Stereoisomerism
Structure-Activity Relationship
Thiosemicarbazones / chemical synthesis*
Thiosemicarbazones / chemistry
Thiosemicarbazones / pharmacology
Transferrin / metabolism

Substances

Antineoplastic Agents
Coordination Complexes
Iron Chelating Agents
Pyridines
Thiosemicarbazones
Transferrin
Iron
Ascorbic Acid