The primary objective of this DPhil research project was to develop selective and cell-active inhibitors of the histone lysine demethylase KDM2A, which could potentially lead to the discovery of a novel chemical probe. Chapter one of this thesis introduces the role of histone lysine demethylases (KDMs) in the epigenetic regulation of gene expression and discusses the value of chemical probes as tools to study these enzymes. Chapter two describes the synthesis of a library of indoline-based KDM2A inhibitors using a modular synthetic approach to explore key structure-activity relationships and a chiral counterion-mediated strategy to synthesize lead candidates enantioselectively. Chapter three discusses investigations into the cellular activity of lead compounds and explores strategies to address limitations associated with cytotoxicity and promiscuity. Chapter four describes the application of a variety of experimental techniques to identify the mode of target inhibition. Finally, chapter five focuses on the development of an enantioselective C-acylation reaction to access spirocyclic fragments asymmetrically.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:730102 |
| Date | January 2016 |
| Creators | Gerken, Philip |
| Contributors | Smith, Martin Derwyn ; Brennan, Paul |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://ora.ox.ac.uk/objects/uuid:8d98e1d6-6a79-4fbc-a04b-776179225498 |
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