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

Bright, Lois Eleanor (2017)
Ph.D. thesis, University of Birmingham.

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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:Ph.D. thesis.
Supervisor(s):Hannon, Michael J. and Hodges, Nik
School/Faculty:Colleges (2008 onwards) > College of Engineering & Physical Sciences
Department:School of Chemistry, PSIBS Doctoral Training Centre
Subjects:QD Chemistry
QH426 Genetics
Institution:University of Birmingham
ID Code:7457
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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