Ligands and complexes for non-covalent binding to G-quadruplex DNA structures

Bright, Lois Eleanor (2017). Ligands and complexes for non-covalent binding to G-quadruplex DNA structures. University of Birmingham. Ph.D.

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Abstract

The structure, occurrence and biological relevance of G-quadruplex DNA structures has been reviewed, along with a review of several notable G-quadruplex binding compounds published in the literature to date. The synthetic route towards two G-quadruplex DNA binders previously developed within the Hannon group has been modified and improved. Electrospray ionisation mass spectrometry studies have been carried out to evaluate nucleotide binding. The in vitro biological activities of these compounds have been validated against the human ovarian carcinoma cell line A2780 via MTT and comet assays, flow cytometry and inductively coupled plasma mass spectrometry. Both compounds and the corresponding metal-free ligand exhibited higher drug efficiencies than cisplatin against A2780 cells. Both compounds display mild genotoxicity and induce G2/M phase cell cycle arrest. The overall cellular uptake and nuclear localisation demonstrated by both complexes exceeds that of cisplatin.

A new class of palladium and platinum(II) complexes have been synthesised from methylthio-substituted terpyridine ligands. In addition to assessing their stability in solution via UV-Vis spectroscopy, initial DNA binding studies with both duplex and quadruplex-forming sequences of DNA have been carried out via circular dichroism and gel electrophoresis.

The design and synthesis of alternative ligand systems proffering a range of desirable characteristics to aid future ligand and complex development has been investigated.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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