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

Bernhardt, P.V., Wilson, G.J., Sharpe, P.C., Kalinowski, D.S. and Richardson, D.R. (2008) 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. Journal of Biological Inorganic Chemistry, 13 1: 107-119. doi:10.1007/s00775-007-0300-4


Author Bernhardt, P.V.
Wilson, G.J.
Sharpe, P.C.
Kalinowski, D.S.
Richardson, D.R.
Title 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
Journal name Journal of Biological Inorganic Chemistry   Check publisher's open access policy
ISSN 0949-8257
Publication date 2008-01-01
Year available 2007
Sub-type Article (original research)
DOI 10.1007/s00775-007-0300-4
Open Access Status
Volume 13
Issue 1
Start page 107
End page 119
Total pages 13
Place of publication Germany
Publisher Springer
Language eng
Subject C1
030201 Bioinorganic Chemistry
970103 Expanding Knowledge in the Chemical Sciences
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.
Keyword Iron chelator
Hydrazone
Cancer
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ
Additional Notes Online November 2007

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Chemistry and Molecular Biosciences
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 50 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 51 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Thu, 19 Mar 2009, 01:34:14 EST by Jennifer Falknau on behalf of School of Chemistry & Molecular Biosciences