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DNA-binding ruthenium complexes : cellular imaging and cytotoxicity
| Content Provider | Semantic Scholar |
|---|---|
| Author | Gill, Martin |
| Copyright Year | 2010 |
| Abstract | The aim of this thesis was to investigate the cellular uptake, in cellulo DNA binding and cytotoxicity of Ru(II) complexes that reversibly bind to DNA in vitro with an accompanying increase in MLCT (metal-to-ligand chargetransfer) luminescence (the DNA light switch effect). Such complexes offer many advantages as luminescent probes of DNA structure but poor cellular uptake restricts their use in live cells. Using a combination of confocal laser scanning microscopy (CLSM) and transmission electron microscopy (TEM), Ru(II)tpphz (tpphz = tetrapyrido[3,2-a:2',3'-c:3'',2''-h:2''',3'''-j]phenazine) metallo-intercalators are shown to be internalised by MCF-7 human breast cancer cells where they successfully target nuclear DNA. Cell viability studies revealed a cytotoxic potency comparable to cisplatin, which is retained for cisplatin-resistant tumour cells. The dinuclear Ru(II)tpphz complex, [{Ru(phen)2}2(tpphz)]4+ [3.1] (phen = 1,10-phenanthroline), was shown to function as a multifunctional biological imaging agent staining the DNA of eukaryotic and prokaryotic cells for both CLSM and TEM while confocal microscopy reveals multiple emission peaks that function as markers for cellular DNA structure. Cell viability studies revealed that [3.1] displays a high toxicity towards cancer cell lines over an extended incubation time, of particular interest as [3.1] binds quadruplex DNA with a high affinity. The synthesis of several derivatives of [3.1], with bpy (2,2'bipyridine), 5mp (5-methyl-phen) and dmp (2,9-dimethyl-phen) replacing phen as the ancillary ligand, has shown how the ancillary ligand can affect such properties as luminescence, DNA binding affinity, cellular uptake and cytotoxicity, which resulted in the derivation of the ancillary ligand “toxicity series” of dmp > phen > 5mp > bpy. Using inhibition studies, a common finding is the uptake mechanism of these Ru(II) complexes is a nonendocytic mode of active transport and nuclear uptake has been shown to be a concentration-dependent process. This work has established the rate of cellular uptake to be the most important factor that governs the cytotoxicity of such complexes and not in vitro DNA binding affinity. List of publications Directly originating from this thesis M. R. Gill, J. Garcia-Lara, S. J. Foster, C. Smythe, G. Battaglia and J. A. Thomas, A ruthenium(II) polypyridyl complex for direct imaging of DNA structure in living cells, Nat. Chem., 2009, 1, 662-667. |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://etheses.whiterose.ac.uk/1161/5/Gill,_M.pdf |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
