Recognition agents for DNA and RNA quadruplex structures

• Main Author: Pritchard, Hannah Louise
• Published: University of Birmingham 2015
• Subjects: 540; QD Chemistry
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.642373

The design and synthesis of a new class of G-quadruplex DNA recognition agents are discussed in this thesis along with their binding abilities to both duplex and G-quadruplex forming DNA. A selection of G-quadruplex binders reported in the literature to date have been reviewed and their interactions with the quadruplex DNA structure analysed. The biisoquinoline ligand used to incorporate into the metal complexes synthesised in this thesis was chosen because of its large aromatic surface area which is ideal for end stacking onto G-quartets. Both the palladium and platinum biisoquinoline complexes bind to quadruplex forming DNA, monitored by UV-vis and circular dichroism. The platinum complex has the most promising DNA binding results showing a selectivity for quadruplex DNA over duplex DNA when examined by gel electrophoresis. Biisoquinoline complex interactions with RNA G-quadruplexes have been investigated to make comparisons of that with DNA. The palladium complex binds less well to parallel quadruplex conformers suggesting its mode of interaction differs from that of the platinum complex. A toxicity assay against two cancer cell lines showed the platinum and palladium complexes to have IC\(_{50}\) values in the nM range. Modifications to the biisoquinoline structure were also attempted in order increase the specificity of the complex to G-quadruplexes by incorporating components that could interact with the quadruplex loops.