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Ruthenium Polypyridyl Complexes in the Exploration of the Chemical Biology of Mismatch DNA / Natália Kolozsvári

Swansea University Author: Natália Kolozsvári

  • E-Thesis under embargo until: 1st July 2026

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...

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Published: Swansea University, Wales, UK 2025
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
first_indexed 2025-07-10T14:52:43Z
last_indexed 2025-07-11T05:02:56Z
id cronfa69946
recordtype RisThesis
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spelling 2025-07-10T16:08:45.7762912 v2 69946 2025-07-10 Ruthenium Polypyridyl Complexes in the Exploration of the Chemical Biology of Mismatch DNA 48502e2203bc676b86f6f9c305a004fe Natália Kolozsvári Natália Kolozsvári true false 2025-07-10 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. E-Thesis Swansea University, Wales, UK DNA mismatch, ruthenium complexes, drug discovery, cancer research 6 6 2025 2025-06-06 10.23889/SUThesis.69946 A selection of content is redacted or is partially redacted from this thesis to protect sensitive and personal information. COLLEGE NANME COLLEGE CODE Swansea University Gill, M. R., and Jenkins, G. J. Doctoral Ph.D School Of Engineering And Applied Sciences Bursaries School Of Engineering And Applied Sciences Bursaries 2025-07-10T16:08:45.7762912 2025-07-10T15:36:01.2068247 Faculty of Science and Engineering School of Engineering and Applied Sciences - Chemistry Natália Kolozsvári 1 Under embargo Under embargo 2025-07-10T15:51:57.4434346 Output 6693893 application/pdf E-Thesis true 2026-07-01T00:00:00.0000000 Copyright: The author, Natália Kolozsvári, 2024 Distributed under the terms of a Creative Commons Attribution 4.0 License (CC BY 4.0). true eng https://creativecommons.org/licenses/by/4.0/
title Ruthenium Polypyridyl Complexes in the Exploration of the Chemical Biology of Mismatch DNA
spellingShingle Ruthenium Polypyridyl Complexes in the Exploration of the Chemical Biology of Mismatch DNA
Natália Kolozsvári
title_short Ruthenium Polypyridyl Complexes in the Exploration of the Chemical Biology of Mismatch DNA
title_full Ruthenium Polypyridyl Complexes in the Exploration of the Chemical Biology of Mismatch DNA
title_fullStr Ruthenium Polypyridyl Complexes in the Exploration of the Chemical Biology of Mismatch DNA
title_full_unstemmed Ruthenium Polypyridyl Complexes in the Exploration of the Chemical Biology of Mismatch DNA
title_sort Ruthenium Polypyridyl Complexes in the Exploration of the Chemical Biology of Mismatch DNA
author_id_str_mv 48502e2203bc676b86f6f9c305a004fe
author_id_fullname_str_mv 48502e2203bc676b86f6f9c305a004fe_***_Natália Kolozsvári
author Natália Kolozsvári
author2 Natália Kolozsvári
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publishDate 2025
institution Swansea University
doi_str_mv 10.23889/SUThesis.69946
college_str Faculty of Science and Engineering
hierarchytype
hierarchy_top_id facultyofscienceandengineering
hierarchy_top_title Faculty of Science and Engineering
hierarchy_parent_id facultyofscienceandengineering
hierarchy_parent_title Faculty of Science and Engineering
department_str School of Engineering and Applied Sciences - Chemistry{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Engineering and Applied Sciences - Chemistry
document_store_str 0
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description 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.
published_date 2025-06-06T14:17:18Z
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score 11.089677

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