Studies on G-quadruplex DNA have grown rapidly due to the potential important roles this type of DNA may play in biology. Stabilisation of telomeric G-quadruplex DNA is thought to inhibit telomerase, an enzyme overexpressed in 85-90 % of cancerous cells. There are also evidences that formation of quadruplex DNA in the promoter region of certain oncogenes (e.g. c-MYC) can suppress their transcription. Therefore, targeting G-quadruplex DNA with small molecules could have interesting applications in cancer therapy. Although most of the quadruplex stabilising molecules reported to date are purely organic G-quadruplex binders, more recently, the ability of metal complexes to stabilise quadruplex DNA has gained more attention due to their unique structural and functional features. The research presented in this thesis aimed at expanding the metal salphen family of complexes to improve affinity and selectivity. The work in this thesis described the design and synthesis of a second generation of nickel(II), copper(II), zinc(II) and platinum (II) salphen complexes to explore the effect of different substituents of the ligand core on quadruplex DNA stabilisation and their selectivity towards quadruplex over duplex DNA. In addition to the above, heteroleptic cycloplatinated complexes have also been prepared in this research to investigate their potential as G-quadruplex DNA stabilisers. Several studies were carried out to elucidate the detailed binding mode between this family of complexes and quadruplex DNA. The interaction between the synthesised metal complexes with G-quadruplex DNA has been examined by means of fluorescent intercalator displacement (FID) assays, UV/Vis DNA titration, circular dichroism (CD) and fluorescence resonance energy transfer (FRET) melting assays. Selected complexes which have shown high quadruplex stabilisation, were co-crystallised with quadruplex DNA. Two X-ray crystal structures have been obtained showing that the metal complexes interact with human telomeric DNA via π-π stacking at the end of G-tetrad.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:555939 |
| Date | January 2012 |
| Creators | Abd Karim, Nurul Huda |
| Contributors | Vilar Compte, Ramon |
| Publisher | Imperial College London |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/10044/1/9658 |
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