Can metal complexes serve as hypoxia activated prodrugs? Investigations of a Co(III) complex of the MMP inhibitor marimastat

Failes, T. W., Diakos, C. I., Underwood, C. K., Hambley, T. W., Cullinane, C. M. and Lyons, J. G. (2003). Can metal complexes serve as hypoxia activated prodrugs? Investigations of a Co(III) complex of the MMP inhibitor marimastat. In: Journal of Inorganic Biochemistry: Abstracts of the 11th International Conference on Biological Inorganic Chemistry. 11th International Conference on Biological Inorganic Chemistry, Cairns, Australia, (128-128). 19 July - 23 July 2003. doi:10.1016/S0162-0134(03)80608-6


Author Failes, T. W.
Diakos, C. I.
Underwood, C. K.
Hambley, T. W.
Cullinane, C. M.
Lyons, J. G.
Title of paper Can metal complexes serve as hypoxia activated prodrugs? Investigations of a Co(III) complex of the MMP inhibitor marimastat
Conference name 11th International Conference on Biological Inorganic Chemistry
Conference location Cairns, Australia
Conference dates 19 July - 23 July 2003
Proceedings title Journal of Inorganic Biochemistry: Abstracts of the 11th International Conference on Biological Inorganic Chemistry   Check publisher's open access policy
Journal name Journal of Inorganic Biochemistry   Check publisher's open access policy
Place of Publication New York
Publisher Elsevier
Publication Year 2003
DOI 10.1016/S0162-0134(03)80608-6
ISSN 0162-0134
Volume 96
Issue 1
Start page 128
End page 128
Total pages 1
Language eng
Abstract/Summary For many years proof that the hypoxic nature of malignant tumours can be used to selectively target anticancer drugs has been sought. Several classes of potential redox activated anticancer drugs have been developed to take advantage of the reducing environment resulting from the hypoxia. Drug complexes with redox active metal centres as carriers have been investigated, but have largely been employed with cytotoxic drugs that require release of the drug intracellularly, complicating the design of such complexes. MMP inhibitors, a new class of anticancer drug, conversely act in the extracellular environment and we have investigated inhibitor complexes with several redox active transition metals. Marimastat is an MMP inhibitor with potent in-vitro antimetastatic activity and was recently in Phase III clinical trials for a variety of cancer types. We have synthesised a Co(II1) complex of marimastat incorporating the tetradentate ligand tpa (tris(2-methylpyridyl)amine) as a carrier ligand. The complex was structurally characterised in the solid state by single crystal X-ray diffraction, the first example of a crystal structure containing marimastat. 2D COSY and NOESY NMR spectra showed that the complex exists in two isomeric forms in solution, corresponding to the cis and trans isomers yet only crystallises in one of these forms. Biological testing of the complex in mice with 4T1.2 tumours showed interesting and unexpected outcomes. Initial results of the tumour growth inhibition study showed that a significant inhibition of growth was exhibited by the complex over the free inhibitor and the control. However, the metastatic potential of both free marimastat and the complex were higher than the control indicating likely problems with the experimental protocol. Further experiments are needed to determine the potential of such complexes as hypoxia activated prodrugs but there appears at least to be some promise.
Subjects 11 Medical and Health Sciences
Keyword Biochemistry & Molecular Biology
Chemistry, Inorganic & Nuclear
Q-Index Code EX
Q-Index Status Provisional Code
Institutional Status Unknown

 
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Created: Mon, 13 Aug 2007, 13:39:20 EST