Tuning the antiproliferative activity of biologically active iron chelators: characterization of the coordination chemistry and biological efficacy of 2-acetylpyridine and 2-benzoylpyridine hydrazone ligands |
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Authors: | Paul V Bernhardt Gregory J Wilson Philip C Sharpe Danuta S Kalinowski Des R Richardson |
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Institution: | (1) Department of Chemistry, Centre for Metals in Biology, University of Queensland, Brisbane, 4072, Australia;(2) Department of Pathology, University of Sydney, Sydney, 2006, Australia |
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Abstract: | 2-Pyridinecarbaldehyde isonicotinoyl hydrazone (HPCIH) and di-2-pyridylketone isonicotinoyl hydrazone (HPKIH) are two Fe chelators
with contrasting biological behavior. HPCIH is a well-tolerated Fe chelator with limited antiproliferative activity that has
potential applications in the treatment of Fe-overload disease. In contrast, the structurally related HPKIH ligand possesses
significant antiproliferative activity against cancer cells. The current work has focused on understanding the mechanisms
of the Fe mobilization and antiproliferative activity of these hydrazone chelators by synthesizing new analogs (based on 2-acetylpyridine
and 2-benzoylpyridine) that resemble both series and examining their Fe coordination and redox chemistry. The Fe mobilization
activity of these compounds is strongly dependent on the hydrophobicity and solution isomeric form of the hydrazone (E or Z). Also, the antiproliferative activity of the hydrazone ligands was shown to be influenced by the redox properties of the
Fe complexes. This indicated that toxic Fenton-derived free radicals are important for the antiproliferative activity for
some hydrazone chelators. In fact, we show that any substitution of the H atom present at the imine C atom of the parent HPCIH
analogs leads to an increase in antiproliferative efficacy owing to an increase in redox activity. These substituents may
deactivate the imine R–C=N–Fe (R is Me, Ph, pyridyl) bond relative to when a H atom is present at this position preventing
nucleophilic attack of hydroxide anion, leading to a reversible redox couple. This investigation describes novel structure–activity
relationships of aroylhydrazone chelators that will be useful in designing new ligands or fine-tuning the activity of others.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. |
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Keywords: | Iron chelator Hydrazone Cancer |
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