Iron chelators of the dipyridylketone thiosemicarbazone class: Precomplexation and transmetalation effects on anticancer activity

Bernhardt, Paul V., Sharpe, Philip C., Islam, Mohammed, Lovejoy, David B., Kalinowski, Danuta S. and Richardson, Des R. (2009) Iron chelators of the dipyridylketone thiosemicarbazone class: Precomplexation and transmetalation effects on anticancer activity. Journal of Medicinal Chemistry, 52 2: 407-415. doi:10.1021/jm801012z


Author Bernhardt, Paul V.
Sharpe, Philip C.
Islam, Mohammed
Lovejoy, David B.
Kalinowski, Danuta S.
Richardson, Des R.
Title Iron chelators of the dipyridylketone thiosemicarbazone class: Precomplexation and transmetalation effects on anticancer activity
Journal name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 0022-2623
Publication date 2009-01-22
Year available 2008
Sub-type Article (original research)
DOI 10.1021/jm801012z
Volume 52
Issue 2
Start page 407
End page 415
Total pages 9
Place of publication United States
Publisher American Chemical Society
Collection year 2009
Language eng
Subject C1
0304 Medicinal and Biomolecular Chemistry
1115 Pharmacology and Pharmaceutical Sciences
Abstract We previously reported a series of di-2-pyridylketone thiosemicarbazone (HDpT) chelators that showed marked and selective antitumor activity (Whitnall, M.; et al. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 14901−14906). To further understand their biological efficacy, we report the characterization and activity of their MnII, CoIII, NiII, CuII, and ZnII complexes. The X-ray crystal structures of four divalent (Mn, Ni, Cu, and Zn) and one trivalent (Fe) complexes are reported. Electrochemistry shows the FeIII/II and CuII/I potentials of the complexes may be redox-active within cells. Stability constants were also determined for the MnII, NiII, CuII, and ZnII complexes. All divalent complexes underwent transmetalation upon encountering FeII, to form low spin ferrous complexes. Importantly, the divalent MnII, NiII, CuII, and ZnII complexes of the HDpT analogues are equally active in preventing proliferation as their ligands, suggesting the complexes act as lipophilic vehicles facilitating intracellular delivery of the free ligand upon metal dissociation.
Keyword Antineoplastic Agents
Cell Proliferation
Crystallography
Q-Index Code C1
Q-Index Status Provisional Code
Additional Notes Publication Date (Web): December 17, 2008

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, 03 Sep 2009, 09:00:02 EST by Mr Andrew Martlew on behalf of Faculty of Science