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Synthesis and reactivity of novel biaryl strained alkynes
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Forshaw, Sam (2022) Synthesis and reactivity of novel biaryl strained alkynes. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b3765834
Abstract
Bioconjugation and bioorthogonality are fields of research which demonstrate potential to revolutionise the way in which biomolecules are studied and drug molecules are delivered. The most promising bioorthogonal reactions are strain promoted azide alkyne cycloadditions. The synthesis of novel strained alkynes and their use as linkers to attach either biomolecules or useful functional groups, such as fluorophores or drug warheads, has been the focus of research since the early 2000s. This has mainly revolved around highly strained cyclooctynes. In this report, the synthesis of novel strained biaryl cyclodecynes will be outlined along with their functional capabilities with various fluorophores and their use as linkers between fluorophores and biomolecules. Fluorescent in vitro imaging of azide labelled GST-F52 with fluorescent derivatives of biaryl cyclodecynes has been successfully attempted along with the synthesis of an azide labelled uracil RNA base. These synthetic RNA bases have been incorporated into RNA strands and shown to react with a commercial alexafluor dye. An investigation into how the structure of biaryl cyclodecynes relates to their reactivity has led to the addition of a four-carbon bridge, creating a new class of highly reactive strained alkynes with second order rate constants between 2.13-62.5 mM-1 s-1. The rate constants expressed by this new class of strained alkynes are comparable to cyclooctynes and difluorinated cyclooctynes. A reactive bipyridyl cyclodecyne, which becomes fluorescent upon reaction with an azide, has been developed and has shown to react at a rate similar to other non-bridged biaryl cyclodecynes. This reactivity is enhanced slightly when Zn(II) is present and fluorescence is also greatly enhanced by the presence of Zn (II). Other metals were investigated; however, no enhanced fluorescence was observed and in some cases fluorescence was diminished.
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QD Chemistry Q Science > QR Microbiology |
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Library of Congress Subject Headings (LCSH): | Alkynes -- Synthesis, Azides, Ring formation (Chemistry), Conjugation (Biology) | ||||
Official Date: | January 2022 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | Department of Chemistry | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | Wills, Martin | ||||
Sponsors: | AstraZeneca (Firm) | ||||
Format of File: | |||||
Extent: | ix, 286 leaves : illustrations | ||||
Language: | eng |
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