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J Med Chem. 2008 May 8;51(9):2787-94. doi: 10.1021/jm7016072. Epub 2008 Apr 16.

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

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  • 1School of Biomedical and Health Sciences, University of Western Sydney, Locked Bag 1797, Penrith South DC, 1797, NSW, Australia.

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 (t 1/2 glutathione: 20 h), degrades fastest, followed by 3 (31 h), 2 (40 h), and 1 (68 h). The major degradation product, [bis-mu-{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.

PMID:
18412325
[PubMed - indexed for MEDLINE]
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