Structure-activity relationships of novel iron chelators for the treatment of iron overload disease: The methyl pyrazinylketone isonicotinoyl hydrazone series

Kalinowski, Danuta S., Sharpe, Philip C., Bernhardt, Paul V. and Richardson, Des R. (2008) Structure-activity relationships of novel iron chelators for the treatment of iron overload disease: The methyl pyrazinylketone isonicotinoyl hydrazone series. Journal of Medicinal Chemistry, 51 2: 331-344. doi:10.1021/jm7012562


Author Kalinowski, Danuta S.
Sharpe, Philip C.
Bernhardt, Paul V.
Richardson, Des R.
Title Structure-activity relationships of novel iron chelators for the treatment of iron overload disease: The methyl pyrazinylketone isonicotinoyl hydrazone series
Journal name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 0022-2623
Publication date 2008-01-01
Year available 2007
Sub-type Article (original research)
DOI 10.1021/jm7012562
Open Access Status DOI
Volume 51
Issue 2
Start page 331
End page 344
Total pages 14
Place of publication United States
Publisher American Chemical Society
Language eng
Subject C1
030201 Bioinorganic Chemistry
970103 Expanding Knowledge in the Chemical Sciences
Abstract The design of novel Fe chelators with high Fe mobilization efficacy and low toxicity remains an important priority for the treatment of Fe overload disease. We have designed and synthesized the novel methyl pyrazinylketone isonicotinoyl hydrazone (HMPIH) analogs based on previously investigated aroylhydrazone chelators. The HMPIH series demonstrated high Fe mobilization efficacy from cells and showed limited to moderate antiproliferative activity. Importantly, this novel series demonstrated irreversible electrochemistry, which was attributed to the electron-withdrawing effects of the noncoordinating pyrazine N-atom. The latter functionality played a major role in forming redox-inactive complexes that prevent reactive oxygen species generation. In fact, the Fe complexes of the HMPIH series prevented the oxidation of ascorbate and hydroxylation of benzoate. We determined that the incorporation of electron-withdrawing groups is an important feature in the design of N,N,O-aroylhydrazones as candidate drugs for the treatment of Fe overload disease.
Keyword Iron
Chelation
Overload
Disease
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
School of Chemistry and Molecular Biosciences
 
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Created: Thu, 19 Mar 2009, 01:09:09 EST by Jennifer Falknau on behalf of Faculty of Science