A Tri-copper(II) Complex Displaying DNA-Cleaving Properties and Antiproliferative Activity against Cancer Cells

A new disubstituted terpyridine ligand and the corresponding tri‐copper(II) complex have been prepared and characterised. The binding affinity and binding mode of this tri‐copper complex (as well as the previously reported mono‐ and di‐copper analogues) towards duplex DNA were determined by using UV...

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Bibliographic Details
Published in:	Chemistry : a European journal Vol. 18; no. 47; pp. 15133 - 15141
Main Authors:	Suntharalingam, Kogularamanan, Hunt, Douglas J., Duarte, Alexandra A., White, Andrew J. P., Mann, David J., Vilar, Ramon
Format:	Journal Article
Language:	English
Published:	Weinheim WILEY-VCH Verlag 19.11.2012 WILEY‐VCH Verlag Wiley Wiley Subscription Services, Inc
Subjects:	Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology cancer Cell Line, Tumor Cell Proliferation - drug effects Chemistry Chemistry, Multidisciplinary Copper Copper - chemistry Crystallography, X-Ray Cytotoxicity Deoxyribonucleic acid DNA DNA - chemistry DNA - drug effects DNA Cleavage Dose-Response Relationship, Drug Drug Screening Assays, Antitumor Enzymes HEK293 Cells Humans Leukemia Models, Molecular Molecular Structure Organometallic Compounds - chemical synthesis Organometallic Compounds - chemistry Organometallic Compounds - pharmacology oxidative cleavage Physical Sciences Science & Technology Structure-Activity Relationship NUCLEASE ACTIVITY DISPLACEMENT ASSAY HISTONE H2AX DOUBLE-STRANDED DNA PLATINUM COMPLEXES PHASE-II TRIAL oxidative cleavage DNA copper DNA cleavage 1,10-PHENANTHROLINE COPPER cancer TRINUCLEAR COPPER COMPLEX G-QUADRUPLEX DNA METAL-COMPLEXES
ISSN:	0947-6539, 1521-3765, 1521-3765
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Summary:	A new disubstituted terpyridine ligand and the corresponding tri‐copper(II) complex have been prepared and characterised. The binding affinity and binding mode of this tri‐copper complex (as well as the previously reported mono‐ and di‐copper analogues) towards duplex DNA were determined by using UV/Vis spectroscopic titrations and fluorescent indicator displacement (FID) assays. These studies showed the three complexes to bind moderately (in the order of 104 M−1) to duplex DNA (ct‐DNA and a 26‐mer sequence). Furthermore, the number of copper centres and the nature of the substituents were found to play a significant role in defining the binding mode (intercalative or groove binding). The nuclease potential of the three complexes was investigated by using circular plasmid DNA as a substrate and analysing the products by agarose‐gel electrophoresis. The cleaving activity was found to be dependent on the number of copper centres present (cleaving potency was in the order: tri‐copper>di‐copper>mono‐copper). Interestingly, the tri‐copper complex was able to cleave DNA without the need of external co‐reductants. As this complex displayed the most promising nuclease properties, cell‐based studies were carried out to establish if there was a direct link between DNA cleavage and cellular toxicity. The tri‐copper complex displayed high cytotoxicity against four cancer cell lines. Of particular interest was that it displayed high cytotoxicity against the cisplatin‐resistant MOLT‐4 leukaemia cell line. Cellular uptake studies showed that the tri‐copper complex was able to enter the cell and more importantly localise in the nucleus. Immunoblotting analysis (used to monitor changes in protein levels related to the DNA damage response pathway) and DNA‐flow cytometric studies suggested that this tri‐copper(II) complex is able to induce cellular DNA damage. Terpyridine ligands: A new tri‐copper(II) complex has been prepared and shown to cleave DNA efficiently without the need for external co‐reductants. The complex displayed a high cytotoxic effect against several cancer‐cell lines including the cisplatin‐resistant MOLT‐4 leukaemia‐cell line (see figure). The complex is cell permeable and a proportion of it localises in the nucleus. Cellular studies demonstrated that this complex induces DNA damage in the cell.
Bibliography:	ark:/67375/WNG-4RP3TZKV-1 ArticleID:CHEM201202482 EPSRC - No. EP/H005285/1 istex:FCD147E4413A7A35FCC5745FA10BF54ED9911E94 Engineering and Physical Sciences Research Council researchfish UKRI ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0947-6539 1521-3765 1521-3765
DOI:	10.1002/chem.201202482