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Studies into the mechanism of action of platinum(II) complexes with potent cytotoxicity in human cancer cells

Krause-Heuer, A.M. and Grunert, R. and Kuhne, S. and Maruszak, M. and Wheate, N.J. and Le Pevelen, D. and Boag, L.R. and Fisher, D.M. (2009) Studies into the mechanism of action of platinum(II) complexes with potent cytotoxicity in human cancer cells. Journal of Medicinal Chemistry, 52 (17). pp. 5474-5484. ISSN 0022-2623

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Abstract

We have examined the biological activity of 12 platinum(II)-based DNA intercalators of the type [Pt(IL)(AL)]2+, where IL is an intercalating ligand (1,10-phenanthroline or a methylated derivative) and AL is an ancillary ligand (diaminocyclohexane, diphenylethylenediamine or 1,2-bis(4-fluorophenyl)-1,2-ethylenediamine). The chiral compounds (1−9) and the racemic compounds (10−12) were tested against a panel of human cancer cell lines, with a number of complexes displaying activity significantly greater than that of cisplatin (up to 100-fold increase in activity in the A-427 cell line). The activity of the complexes containing diphenylethylenediamine (8 and 9) and 1,2-bis(4-fluorophenyl)-1,2-ethylenediamine (10−12) was significantly lower compared to the complexes containing diaminocyclohexane (1−7). Further in vitro testing, such as DNA unwinding, competition assays, and DNase 1 footprinting, was conducted on the most active compound (5) and its enantiomer (6) to provide information about the mechanism of action. These complexes display activity in cisplatin resistant cell lines, have higher cellular uptake than cisplatin, and do not activate caspase-3 as cisplatin does, indicating that these complexes exhibit a different mechanism of action.

Item type: Article
ID code: 26046
Notes: Strathprints' policy is to record up to 8 authors per publication, plus any additional authors based at the University of Strathclyde. More authors may be listed on the official publication than appear in the Strathprints' record.
Keywords: platinum, cytotoxicity, human cancer cells, cancer, pharmacology, Therapeutics. Pharmacology, Drug Discovery, Molecular Medicine
Subjects: Medicine > Therapeutics. Pharmacology
Department: Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
Faculty of Engineering > National Centre for Prosthetics and Orthotics
Related URLs:
    Depositing user: Strathprints Administrator
    Date Deposited: 31 Aug 2010 11:10
    Last modified: 05 Sep 2014 05:17
    URI: http://strathprints.strath.ac.uk/id/eprint/26046

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