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Cytotoxic iron chelators: characterization of the structure, solution chemistry and redox activity of ligands and iron complexes of the di-2-pyridyl ketone isonicotinoyl hydrazone (HPKIH) analogues

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Abstract

Di-2-pyridyl ketone isonicotinoyl hydrazone (HPKIH) and a range of its analogues comprise a series of monobasic acids that are capable of binding iron (Fe) as tridentate (N,N,O) ligands. Recently, we have shown that these chelators are highly cytotoxic, but show selective activity against cancer cells. Particularly interesting was the fact that cytotoxicity of the HPKIH analogues is maintained even after complexation with Fe. To understand the potent anti-tumor activity of these compounds, we have fully characterized their chemical properties. This included examination of the solution chemistry and X-ray crystal structures of both the ligands and Fe complexes from this class and the ability of these complexes to mediate redox reactions. Potentiometric titrations demonstrated that all chelators are present predominantly in their charge-neutral form at physiological pH (7.4), allowing access across biological membranes. Keto–enol tautomerism of the ligands was identified, with the tautomers exhibiting distinctly different protonation constants. Interestingly, the chelators form low-spin (diamagnetic) divalent Fe complexes in solution. The chelators form distorted octahedral complexes with FeII, with two tridentate ligands arranged in a meridional fashion. Electrochemistry of the Fe complexes in both aqueous and non-aqueous solutions revealed that the complexes are oxidized to their ferric form at relatively high potentials, but this oxidation is coupled to a rapid reaction with water to form a hydrated (carbinolamine) derivative, leading to irreversible electrochemistry. The Fe complexes of the HPKIH analogues caused marked DNA degradation in the presence of hydrogen peroxide. This observation confirms that Fe complexes from the HPKIH series mediate Fenton chemistry and do not repel DNA. Collectively, studies on the solution chemistry and structure of these HPKIH analogues indicate that they can bind cellular Fe and enhance its redox activity, resulting in oxidative damage to vital biomolecules.

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Abbreviations

DFO:

desferrioxamine

HPKIH:

di-2-pyridyl ketone isonicotinoyl hydrazone

HNIH:

2-hydroxy-1-naphthaldehyde isonicotinoyl hydrazone

HPCIH:

2-pyridinecarbaldehyde isonicotinoyl hydrazone

HPIH:

pyridoxal isonicotinoyl hydrazone

L:

linear DNA

OC:

open circular DNA

SC:

supercoiled DNA

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Acknowledgements

The Children’s Cancer Institute Australia for Medical Research is affiliated with the University of New South Wales and Sydney Children’s Hospital. This project was supported by a fellowship and projects grant from the National Health and Medical Research Council of Australia (D.R.R.) and an Australian Research Council Large Grant (D.R.R.). T.B.C. thanks the Friedreich’s Ataxia Foundation of New South Wales and Victoria for a PhD Scholarship. P.V.B. acknowledges financial support from the University of Queensland.

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Authors and Affiliations

  1. Department of Chemistry, University of Queensland, 4072, Brisbane, Australia

    Paul V. Bernhardt, Lorraine M. Caldwell & Piao Chin

  2. Children’s Cancer Institute Australia for Medical Research, High Street, Randwick, PO Box 81, 2031, Sydney, NSW, Australia

    Timothy B. Chaston & Des R. Richardson

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  1. Paul V. Bernhardt
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  2. Lorraine M. Caldwell
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  3. Timothy B. Chaston
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  4. Piao Chin
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  5. Des R. Richardson
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Correspondence to Paul V. Bernhardt or Des R. Richardson.

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Bernhardt, P.V., Caldwell, L.M., Chaston, T.B. et al. Cytotoxic iron chelators: characterization of the structure, solution chemistry and redox activity of ligands and iron complexes of the di-2-pyridyl ketone isonicotinoyl hydrazone (HPKIH) analogues. J Biol Inorg Chem 8, 866–880 (2003). https://doi.org/10.1007/s00775-003-0486-z

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