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Title: Varying the electronic properties of metal salphens and studying their effects on DNA binding
Author: Reynolds, Matthew Thomas
ISNI:       0000 0004 8504 4212
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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G-quadruplexes are a non-canonical form of DNA, which have the potential to form in guanine rich oligonucleotides under physiological conditions. High-throughput sequencing studies have indicated ca. 716000 putative G-quadruplex forming sequences within the human genome. These are mainly located in the telomeres, and promoter regions of certain proto-oncogenes, such as c-Myc and c-KIT. Several recent studies have added to the mounting evidence of their existence in vivo, including visualisation with optical probes, and detection using chromatin immunoprecipitation experiments. Their proposed existence and location within the genome makes them an attractive target for anti-cancer therapy. Many groups have sought to design small molecule drugs to stabilise G-quadruplexes in vivo. Our group has focussed mainly on designing Schiff base salphen complexes to selectively interact with G-quadruplexes. However, minimal work has been done to investigate the dependence of G-quadruplex binding on electron-directing affects around the salicylidene rings. The work presented herein shows the synthesis of novel salphen complexes that demonstrate good selectivity for G-quadruplexes over duplex DNA. No firm conclusions could be made regarding the effect of electron-directing groups, due in part to the limited number of complexes comprising this series, but also due to the unexpectedly high G-quadruplex affinity of a complex with strongly electron-donating substituents. The results of an investigation into metal centre variation - and consequently complex geometry - broadly agree with results from literature. We also sought to improve the G-quadruplex model used in many of the in vitro studies of G-quadruplex-ligand binding interactions. An alternative model, the 'G-quadruplex mini-circle', was optimised for use in a novel kinetic study. The modifications made to this model greatly affected the kinetics of G-quadruplex unfolding, supporting our case that the present model is an unsuitable mimetic of cellular nucleic acids. This model was tested further using a range of established G-quadruplex ligands.
Supervisor: Vilar, Ramon Sponsor: Engineering and Physical Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral