Cobalt complexes with tripodal ligands: implications for the design of drug chaperones

Bonnitcha, Paul D., Kim, Byung J., Hocking, Rosalie K., Clegg, Jack K., Turner, Peter, Neville, Suzanne M. and Hambley, Trevor W. (2012) Cobalt complexes with tripodal ligands: implications for the design of drug chaperones. Dalton Transactions, 41 37: 11293-11304. doi:10.1039/C2DT30727H

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Author Bonnitcha, Paul D.
Kim, Byung J.
Hocking, Rosalie K.
Clegg, Jack K.
Turner, Peter
Neville, Suzanne M.
Hambley, Trevor W.
Title Cobalt complexes with tripodal ligands: implications for the design of drug chaperones
Journal name Dalton Transactions   Check publisher's open access policy
ISSN 1477-9226
1477-9234
Publication date 2012-10-07
Sub-type Article (original research)
DOI 10.1039/C2DT30727H
Open Access Status File (Publisher version)
Volume 41
Issue 37
Start page 11293
End page 11304
Total pages 12
Place of publication Cambridge, United Kingdom
Publisher RSC
Collection year 2013
Language eng
Abstract Extensive research is currently being conducted into metal complexes that can selectively deliver cytotoxins to hypoxic regions in tumours. The development of pharmacologically suitable agents requires an understanding of appropriate ligand–metal systems for chaperoning cytotoxins. In this study, cobalt complexes with tripodal tren (tris-(2-aminoethyl)amine) and tpa (tris-(2 pyridylmethyl)amine) ligands were prepared with ancillary hydroxamic acid, β-diketone and catechol ligands and several parameters, including: pKa, reduction potential and cytotoxicity were investigated. Fluorescence studies demonstrated that only tpa complexes with β-diketones showed any reduction by ascorbate in situ and similarly, cellular cytotoxicity results demonstrated that ligation to cobalt masked the cytotoxicity of the ancillary groups in all complexes except the tpa diketone derivative [Co(naac)tpa](ClO4)2 (naac = 1-methyl-3-(2-naphthyl)- propane-1,3-dione). Additionally, it was shown that the hydroxamic acid complexes could be isolated in both the hydroxamate and hydroximate form and the pKa values (5.3–8.5) reveal that the reversible protonation/deprotonation of the complexes occurs at physiologically relevant pHs. These results have clear implications for the future design of prodrugs using cobalt moieties as chaperones, providing a basis for the design of cobalt complexes that are both more readily reduced and more readily taken up by cells in hypoxic and acidic environments.
Keyword Metal complexes
Cytotoxins
Hypoxic regions
Tumour
Chaperoning
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes First published on the web: 28 June 2012.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
School of Chemistry and Molecular Biosciences
 
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Created: Wed, 03 Oct 2012, 10:10:48 EST by Mrs Louise Nimwegen on behalf of School of Chemistry & Molecular Biosciences