Bradford Scholars -how to deposit your paper
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Bradford Scholars -how to deposit your paper
Overview
Copyright check• Check if your publisher allows submission to a repository.• Use the Sherpa RoMEO database if you are not sure about your publisher's position or email openaccess@bradford.ac.uk.
YesEnantiomers of a relatively rigid DNA-binding metallo-helix are shown to have comparable activity to that\ud
of cisplatin against the cell lines MCF7 (human breast adenocarcinoma) and A2780 (human ovarian\ud
carcinoma) but are ca five times more active against the cisplatin-resistant A2780cis. The cell-line\ud
HCT116 p53+/+ (human colon carcinoma) is highly sensitive giving IC50 values in the nM range, far lower\ud
than the cisplatin control. The hypothesis that the biological target of such metallohelices is DNA is\ud
probed by various techniques. Tertiary structure changes in ct-DNA (formation of loops and\ud
intramolecular coiling) on exposure to the compounds are demonstrated by atomic force microscopy\ud
and supported by circular/linear dichroism in solution. Selectivity for 50-CACATA and 50-CACTAT\ud
segments is shown by DNase I footprinting. Various three- and four-way oligonucleotide junctions are\ud
stabilised, and remarkably only the L metallo-helix enantiomer stabilizes T-shaped 3WJs during gel\ud
electrophoresis; this is despite the lack of a known helix binding site. In studies with oligonucleotide\ud
duplexes with bulges it is also shown for the first time that the metallo-helix binding strength and the\ud
number of binding sites are dependent on the size of the bulge. In contrast to all the above, flexible\ud
metallo-helices show little propensity for structured or selective DNA binding, and while for A2780 the\ud
cancer cell line cytotoxicity is retained the A2780cis strain shows significant resistance. For all\ud
compounds in the study, H2AX FACS assays on HCT116 p53+/+ showed that no significant DNA damage\ud
occurs. In contrast, cell cycle analysis shows that the DNA binders arrest cells in the G2/mitosis phase,\ud
and while all compounds cause apoptosis, the DNA binders have the greater effect. Taken together\ud
these screening and mechanistic results are consistent with the more rigid helices acting via a DNA\ud
binding mechanism while the flexible assemblies do not
A series of ruthenium and iridium complexes have been synthesised and characterised with 20 novel crystal structures discussed. The library of -ketoiminato complexes has been shown to be active against MCF-7 (human breast carcinoma), HT-29 (human colon carcinoma), A2780 (human ovarian carcinoma) and A2780cis (cisplatin resistant human ovarian carcinoma) cell lines, with selected complexes being more than three times as active as cisplatin against the A2780cis cell line. Complexes have also been shown to be highly active under hypoxic conditions, with the activities of some complexes increasing with a decrease in O2 concentration. The enzyme thioredoxin reductase is over-expressed in cancer cells and complexes reported herein have the advantage of inhibiting this enzyme, with IC50 values measured in the nanomolar range. The anti-cancer activity of these complexes was further investigated to determine whether activity is due to effects on cellular growth or cell survival. The complexes were found to induce significant cancer cell death by apoptosis with levels induced correlating closely with activity in chemosensitivity studies. As a possible cause of cell death, the ability of the complexes to induce damage to cellular DNA was also assessed. The complexes failed to induce double strand DNA break or DNA crosslinking but induced significant levels of single DNA strand breaks indicating a different mechanism of action to cisplatin.
Rianne M. Lord obtained her Ph.D. degree in chemistry in 2014 under the supervision of Professor Patrick C. McGowan at the University of Leeds (U.K.). Following this, she joined the research team of Professor Polly L. Arnold at the University of Edinburgh (U.K.) as a postdoctoral research associate. In 2016, Rianne began her independent career as a lecturer of bioinorganic chemistry at the University of Bradford (U.K.) and currently holds an August-Wilhelm Scheer visiting professorship at the Technische Universität München (Germany). Her research interests focus on the development of new transition metal cancer therapeutics and designing effective drug delivery systems.
A library of new bis-picolinamide ruthenium(III) dihalide complexes of the type RuX2L2 (X = Cl or I and L = picolinamide) have been synthesised and characterised. They exhibit different picolinamide ligand binding modes, whereby one ligand is bound (N,N) and the other bound (N,O). Structural studies reveal a mixture of cis and trans isomers for the RuCl2L2 complexes but upon a halide exchange reaction to RuI2L2, only single trans isomers are present. High cytotoxic activity against human cancer cell lines was observed, with potencies for some complexes similar to or better than cisplatin. Conversion to RuI2L2 substantially increased activity towards cancer cell lines by >12-fold. The RuI2L2 complexes displayed potent activity against the A2780cis (cisplatin-resistant human ovarian cancer) cell line, with >4-fold higher potency than cisplatin. Equitoxic activity was observed against normoxic and hypoxic cancer cells, indicating the potential to eradicate both the hypoxic and aerobic fractions of solid tumours with similar efficiency. Selected complexes were also tested against non-cancer ARPE-19 cells. The RuI2L2 complexes are more potent than the RuCl2L2 analogues, and also more selective towards cancer cells with a selectivity factor >7-fold.
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