E-Thesis 293 views
Ruthenium Polypyridyl Complexes in the Exploration of the Chemical Biology of Mismatch DNA / Natália Kolozsvári
Swansea University Author: Natália Kolozsvári
DOI (Published version): 10.23889/SUThesis.69946
Abstract
The aim of this thesis was the synthesis and characterisation of novel ruthenium polypyridyl complexes employing the “elbow-shaped” qdppz (qdppz = naphtho[2,3-a]dipyrido[3,2-h:2‘,3‘-f]phenazine-5,18-dione) intercalating ligand and different, bipyridyl- (bpy) or phenanthroline-based (phen) ancillary...
| Published: |
Swansea University, Wales, UK
2025
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| Institution: | Swansea University |
| Degree level: | Doctoral |
| Degree name: | Ph.D |
| Supervisor: | Gill, M. R., and Jenkins, G. J. |
| URI: | https://cronfa.swan.ac.uk/Record/cronfa69946 |
| Abstract: |
The aim of this thesis was the synthesis and characterisation of novel ruthenium polypyridyl complexes employing the “elbow-shaped” qdppz (qdppz = naphtho[2,3-a]dipyrido[3,2-h:2‘,3‘-f]phenazine-5,18-dione) intercalating ligand and different, bipyridyl- (bpy) or phenanthroline-based (phen) ancillary ligands, with systematically varying methylation. The large planar qdppz ligand was expected to provide higher DNA mismatch-binding affinity and a similar effect of methylation of the ancillary ligands was also investigated. Using UV-Vis titration to quantify DNA-binding ability, it was determined that dimethylation at the 4,4’ position decreases, while dimethylation at the 5,5’ position increases binding affinity. Employing an adapted ethidium bromide displacement assay to investigate selectivity towards mismatches in DNA,[Ru(5,5’-dmbpy)2(qdppz)]2+ (complex 4) was identified as an excellent mismatch-binder with significantly higher affinity towards six different mismatched base pairs compared to well-matched control sequences. Supporting this, specific targeting of the CC mismatch was demonstrated through elevated quenching efficiency of the Cyanine5.5 luminescent dye attached to a DNA oligomer as a function of mismatch proximity to the dye. In vitro cellular assays identified complex 4 as a highly cytotoxic compound in the mismatch repair (MMR)-deficient DLD-1 colorectal cancer cell line, as well as its MMR-restored counterpart,DLD-1+Chr2; however, against expectations, no selectivity towards the MMR-deficient cell line was observed. Further testing demonstrated a moderate anti-proliferative effect in DLD-1 cells upon treatment with complex 4, but no significantly elevated rate of DNA damage, cell cycle disruption or apoptosis was observed. This work has shown that non-luminescent qdppz-containing complexes are excellent mismatch-binders whose properties can be significantly influenced by methylation on the ancillary ligands, including inducing elevated cytotoxicity against DLD-1 colorectal cancer cells. |
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| Item Description: |
A selection of content is redacted or is partially redacted from this thesis to protect sensitive and personal information. |
| Keywords: |
DNA mismatch, ruthenium complexes, drug discovery, cancer research |
| College: |
Faculty of Science and Engineering |
| Funders: |
School Of Engineering And Applied Sciences Bursaries |