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The Strathprints institutional repository is a digital archive of University of Strathclyde's Open Access research outputs. Strathprints provides access to thousands of Open Access research papers by University of Strathclyde researchers, including by researchers from the Department of Computer & Information Sciences involved in mathematically structured programming, similarity and metric search, computer security, software systems, combinatronics and digital health.

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Degradation of bidentate-coordinated platinum(II)-based DNA intercalators by reduced l-glutathione

Kemp, S. and Wheate, N.J. and Pisani, Michelle J. and Aldrich-Wright, J.R. (2008) Degradation of bidentate-coordinated platinum(II)-based DNA intercalators by reduced l-glutathione. Journal of Medicinal Chemistry, 51 (9). pp. 2787-2794. ISSN 0022-2623

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Abstract

We have examined the interaction of [(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)platinum(II)]2+ (1, 56MESS), [(5-methyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)platinum(II)]2+ (2, 5MESS), [(5,6-dimethyl-1,10-phenanthroline)(1R,2R-diaminocyclohexane)platinum(II)]2+ (3, 56MERR), and [(5,6-dimethyl-1,10-phenanthroline)(ethylenediamine)platinum(II)]2+ (4, 56MEEN) with reduced l-glutathione and l-methionine. Both thiols degrade all four complexes, mainly by displacing the ancillary ligand and forming a doubly bridged dinuclear complex. The degradation half-life of all the complexes with methionine is >7 days, indicating that these reactions are not biologically relevant. The rate of degradation by glutathione appears to be particularly important and shows an inverse correlation to cytotoxicity. The least active complex, 4 (t1/2 glutathione: 20 h), degrades fastest, followed by 3 (31 h), 2 (40 h), and 1 (68 h). The major degradation product, [bis-μ-{reduced l-glutathione}bis{5,6-dimethyl-1,10-phenanthroline}bis{platinum(II)}]2+ (5, 56MEGL), displays no cytotoxicity and is excluded as the source of the anticancer activity. Once bound by glutathione, these metal complexes do not then form coordinate bonds with guanosine. Partial encapsulation of the complexes within cucurbit[n]urils is able to stop the degradation process.