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Title: The synthesis of procyanidin B3 and heterocycle-linked oligonucleotides
Author: Alharthy, Rima D.
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2013
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Abstract:
The first section of this thesis describes the synthesis of procyanidin B3, a dimeric flavanoid consists of monomeric (+}-catechin and a member of the polyphenol family. A study of the leaving groups at C4 catechin together with Lewis acid activator effects on the formation of the interflavan hond formation was conducted. A range of electrophilic ethers was prepared via DDQ oxidation and a1coholic trapping (propanol, crotyl a1rohol and propargyl alcohol) at the C4 position of (+}-catechin. The Lewis acid-mediated nucleophilic C4 substitution of each of these ethers was examined and it was found that the propargyl ether was the best overall e1ectrophile. A range of Lewis acids were then examined as activators and it was found that BF3oOEt2 was the best in terms of both yield and stereochemical control at the C4 position. In our view, the strength of the nucleophiles used contributed mainly to the diastereoselectivity preference for the substitution reactions. This newly developed set of conditions was then used to prepare the natural product nutraceutical procyanidin B3 with high control of diastereoselectivity. To extend the versatility of this synthesis, a novel dimeric polyphenol analogue was synthesised utilising the optimum conditions used for the synthesis of pro cyanidin B3. The second section of this thesis is devoted to the synthesis of novel morpholino antisense oligonucleotides. Herein, the synthesis of amine and amide triazolelinked Morpholinos (TI.Morpholinos) using click copper-catalysed Huisgen [3 + 2] cycloaddition is illustrated. Replacing the charged phosphodiester backbone with a neutral, achiral 1.2.3-triazole linkage was chosen to improve the biostability in antisense applications. The synthesis of terminal alkyne morpholinos and examples of azide monomers required for the click chemistry was successfully achieved. The synthesis presented in this work tolerated a range of functionalities and was amenable to all nucleosides. The amine and amide TI.Morpholino oligonucleotides were constructed using the standard solid-phase DNA synthesis. Both the amine and amide TLMorpholinos formed were characterised by MALDITOF and HPLC experiments. The thermal stability of the amine and amide TI.Morpholinos relative to a standard DNA was assessed and it was found that the amine and amide triazole linkages stabilised the DNA duplex. It was concluded that these modifications enhanced the stability of the DNA duplex and consequently might contribute to the development of new candidates for the antisense applications
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.594244  DOI: Not available
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