This thesis details the synthesis of self-immolative linkers based on 1 ,4-disubstituted-1 H-1,2,3- triazoles prepared via copper catalysed [3+2] azide-alkyne cycloaddition chemistry and their degradability as a function of pH. Their application to aqueous soluble polymer conjugates was also demonstrated. This thesis is divided into five chapters and an appendix. Chapter 1 provides an introduction to the theory of self-immolative elimination, and discusses the types of self-immolative linkers developed and their application to the controlled release of drug, sensor and fragrance molecules. The discussion has focused on the occurrence and use of self-immolative linkers in both biological and synthetic polymer conjugates and their release characteristics. Chapter 2 details the synthesis of a range of structurally diverse carbamate, carbonate and ether functionalised self- immolative triazoles bearing model fragrances or fragrance surrogates. A range of organic azide, and carbamate, carbonate and ether functionalised alkyne precursors were synthesised and methodologies optimised. Optimisation of the subsequent copper catalysed [3+2] azide-alkyne cycloaddition reaction was also conducted. Furthermore, a range of analytical standards were prepared for a comparative study aimed to identify, and differentiate between, degradation pathways. Chapter 3 depicts the degradation studies conducted on the self-immolative triazole linkers prepared . in Chapter 2. The acid and/or base sensitivity of these compounds were determined using a standardised methodology, and their labilities compared within, and across, each series. NMR spectroscopy was utilised to gather kinetic data with which structure-activity relationships could be highlighted and quantified. The analytical standards synthesised in Chapter 2 were utilised to positively identify reaction intermediates and product fragments. These analyses led to the proposal, and subsequent discussion of reaction mechanisms. Chapter 4 describes the synthesis of a range of polymers prepared by atom-transfer radical polymerisation featuring self-immolative triazole tethers. Firstly, a range of methodologies to obtain azide containing polymers were explored. Initiator, catalyst and solvent systems were optimised for each series. The copper catalysed [3+2] cycloaddition was examined using a range of synthesised polymers, and the lead material subjected to a degradation study. The 'staged-release' of multiple components under acidic conditions was demonstrated utilising analogous conditions to those developed in Chapter 3. Chapter 5 provides experimental details and analytical data for the small molecule compounds synthesised in Chapter 2, the degradation experiments conducted in Chapter 3 and polymeric materials synthesised in Chapter 4.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:558761 |
| Date | January 2012 |
| Creators | Blencowe, Christopher |
| Publisher | University of Reading |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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