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Title: A study of synthetic routes to pyridine-stretched nucleoside analogues
Author: Crawford, Julia Ann.
Awarding Body: University of Keele
Current Institution: Keele University
Date of Award: 2004
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An introduction to the use of oligonucleotides as antigene or antisense therapeutic agents is presented. This includes an analysis of the major areas of structural change implemented to improve the stability, specificity, nuclease resistance and cellular delivery of oligonucleotides. The synthetic aspect of the project concerns the preparation of two novel 'pyridinestretched' heterocyclic bases principally designed to improve base stacking. The first of these, 8-amino-3 -(2-deoxy-J3-D-ribofuranosyl)-imidazo [4' ,5': 5 ,6]pyrido[2,3-d]pyrimidine, is a stretched adenosine analogue which may be synthesised in eight stages from the starting materials 2-deoxY-D-ribose and 5-nitroimidazole. The protection reactions required to prepare the nucleoside for incorporation into an oligonucleotide are then addressed. Protection of the amino group is conveniently achieved using N,Ndimethylacetamide dimethyl acetal. Protection of the sugar hydroxyl groups is subject to steric hindrance from the stretched base and requires further investigation. Synthesis of the second 'pyridine-stretched' purine analogue 2,3-dimethyl-9- methylsulfanyl-3H-I ,3,4,5, 7-pentaaza-cyclopenta[ b ]naphthalene-8-ylamine proceeds with the aim of isolating one intermediate that can further be modified through the use of simple nucleophilic substitution reactions. Protection of the exocyclic amino group followed by oxidation of the methyl sulfanyl group to the equivalent sulfone facilitates altering the substituents at position nine on the cyclic ring system. The sui phone is readily displaced by nucleophiles giving a simple route to the isolation of further diverse analogues
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: null Biosynthesis Nucleosides Antigens and antibodies Oligonucleotides