Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.779402
Title: Synthesis of chemical tools for targeted epigenetic modifications
Author: Nguyen, Ha Phuong
ISNI:       0000 0004 7965 0988
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2019
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Abstract:
DNA methylation is an important epigenetic modification that regulates gene expression, thereby playing a crucial role in biological processes including cellular development but also disease progression. Abnormal methylation patterns such as gene promoter hypermethylation are the most common molecular lesions found in cancer. Since DNA methylation is a reversible process, DNA methyltransferases (DNMTs) - the enzymes responsible for the maintenance of methylation patterns - are regarded as very attractive therapeutic targets. To date, several DNMT inhibitors have been developed to reverse DNA hypermethylation. The clinically approved azanucleosides 5-azacytidine and 5-aza-2'-deoxycytidine have high demethylating potency, but their use has remained limited due to their nonspecific activity and cytotoxic side-effects. The lack of techniques for targeted tissue-specific demethylation not only limits therapeutic potential but also restricts our understanding of the functional significance of DNA methylation in a number of biological processes, including cellular development and regeneration. The aim of this thesis was to develop small molecule tools that could achieve spatiotemporally targeted demethylation through light-based activation. We have used a photocaging strategy to synthesise six novel photocaged azanucleoside analogues. These analogues remained biologically inert until light illumination induced the release of active azanucleosides with moderate-to-high rates and efficiencies. It was found that the caging position strongly influenced the photochemical properties and aqueous stabilities of the photocaged analogues. The analogue with the fastest uncaging rate and best aqueous stability 3'-DEACMOC-dAC was evaluated for its biological performance in a number of cancer cell lines. Global DNA methylation analysis showed that the analogue achieved light-dependent demethylation at lower concentration treatments. However, at higher concentrations unexpected activity was observed in the absence of light, prompting further investigation using mass spectrometry analysis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.779402  DOI: Not available
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