Jarvis, Katherine; (2010) Synthesis and evaluation of some tricyclic small molecules as G-quadruplex targeting agents. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Guanine rich regions of DNA can form higher-order G-quadruplex structures, G-quadrupiex forming sequences have been found in telomeric DNA and also in regulatory regions of oncogenes such as c-kit. The stabilisation of these structures by small molecules is considered to be a chemotherapeutic target, in telomeres through the inhibition of the action of telomerase leading to telomere shortening, growth arrest, senescence and apoptosis of tumour cells, and in oncogenes leading to selective inhibition of gene expression. Three series of tricyclic small molecules have been designed and synthesised as G-quadruplex interactive agents. The compounds synthesised contain a variety of side chains incorporating positive charge attached to the core, to enhance affinity, selectivity and aqueous solubility. Compounds were evaluated for their ability to stabilise a panel of G-quadruplex and duplex DNAs using a high-throughput florescence resonance energy transfer (FRET) based method, and for their cytotoxicity effects against a panel of cancer and normal fibroblast cell lines. A gastrointestinal stromal tumor (GIST) cell line was also investigated which lead to the examination of two quadruplex forming sequences from the promoter region of the c-kit oncogene. The first series are composed of a phenoxazinone chromophore and peptide side chains based on a previously identified sequence (Arg-Lys-Lys-Val). Various peptide side chains have been synthesised by solid phase peptide synthesis and attached to the phenoxazinone core. The results show some stabilisation of telomeric and c-kit-2 G-quadruplexes, however little selectivity is seen as the most effective ligands also show some interaction with duplex DNA. The second series is also based on the phenoxazinone chromophore, the side chains are non-peptidic and contain tertiary amines which will be positively charged at physiological pH. Some of the ligand side chains contain a triazole ring connected via a benzene ring to the core. These ligands have been synthesised via click chemistry allowing the easy incorporation of diversity into the series. The DNA melting stabilisation results show some ligands with a high level of stabilisation of the telomeric and c-kit-2 quadruplexes. The triazole-containing ligands also show a high level of selectivity with little interaction with duplex DNA, and this is reflected in their cytotoxicity. The third series is based on the anthraquinone core with the addition of side chains containing the hydroxy piperidine end group. The results of DNA melting studies show stabilisation of a range of G-quadruplexes including the c-kit-1 quadruplex. Again however these ligands lack selectivity and thus show a high level of cytotoxicity.

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