High triarylpyridine affinity towards a parallel G-quadruplex in the c-kit promoter

Research output: ThesisDoctoral Thesis

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Abstract

[Truncated abstract] G-quadruplex DNA is an attractive target for anti-cancer therapy as the occurrence of guanine rich (G-rich) sequences that can potentially form quadruplexes, within the human and other genomes, are over-represented in promoter regions of genes involved in replication, such as oncogenes, and at the 3′-end of telomeric DNA which is maintained in length in 90% of cancers by the reverse transcriptase enzyme, telomerase. Some small molecules that bind and stabilize the G-quadruplex structure have been shown to downregulate oncogene expression and induce telomere disruption. 2,4,6-Triarylpyridines with amidoalkylamino side-chains were envisaged to serve as promising in situ protonated Gquadruplex DNA ligands as the pyridine functionality is present in some of the best small molecule G-quadruplex ligands. The triarylpyridine chromophore would be prone to π- stacking interactions with the terminal G-quartet of the G-quadruplex and the in situ protonated side-chains may engage in electrostatic interactions with the loops and grooves of the G-quadruplex. The utility of PEG (polyethylene glycol) as a reaction medium for preparing key aminofunctionalised 2,4,6-triarylpyridines in 'one-pot' has been established. The process is tolerant of the unprotected amino groups, in contrast to the solventless procedure, which proceeds poorly with competing Schiff base formation. This base catalysed 'one pot' approach for making amino-substituted pyridines of this type is without precedent. The ensuing compounds have exciting possibilities in a wide range of applications from biology to materials science, where there is the ability to build a diverse array of compounds by using potentially three directionalities associated with the pyridine core. Moreover, the use of PEG to affect chemical transformations in a more simplified and benign way further highlights its potential as an alternative reaction medium, in both controlling chemical reactivity and avoiding
Original languageEnglish
QualificationDoctor of Philosophy
Publication statusUnpublished - 2009

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