Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.339706
Title: Nucleoside and oligonucleotide approaches towards potential HIV chemotherapies
Author: Wallis, Mark P.
Awarding Body: Aston University
Current Institution: Aston University
Date of Award: 1996
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Abstract:
The use of oligonucleotides directed against the mRNA of HIV promises site-specific inhibition of viral replication. In this work, the effect of aralkyl substituents on oligonucleotide duplex stability was studied using model oligonucleotide sequences in an attempt to improve targeting of oligonucleotides to viral mRNA. Arakyl-substituted oligonucleotides were made by solid phase synthesis using either the appropriate aralkyl-substituted phosphoramidite or by post-synthetic substitution of a pentafluorophenoxy substituent by N-methylphenethylamine. The presence of phenethyl or benzoyl substituents invariably resulted in thermodynamic destabilisation of all duplexes studied. The methods which were developed for the synthesis of nucleoside intermediates for oligonucleotide applications were also used to prepare a series of nucleoside analogues derived from uridine, 2'-deoxyuridine and AZT. Crystal structures of six compounds were successfully determined. Anti-HIV activity was observed for most compounds in the series although none were without cytotoxicity. The most active compound of the series was the ribose nucleoside; 1--D-erythro-pentofuranosyl-4-pentafluorophenoxy-pyrimidine-2(1H)-one 95, derived directly from uridine. The same series of compounds also displayed very modest anti-cancer activity. To enable synthesis of prooligonucleotides and analogues for possible antisense applications, the properties of a new Silyl-Linked Controlled Pore Glass solid support were investigated. Synthesis of the sequences d(Tp)7T, d(Tps)7T and the base-sensitive d(Tp)3(CBzp)2(Tp)2T was achieved using the silyl-linked solid support in a fluoride-induced cleavage/deprotection strategy.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Phd
EThOS ID: uk.bl.ethos.339706  DOI: Not available
Keywords: Pharmacy ; Biological Sciences Pharmacology Biochemistry
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