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Title: The synthesis of bicyclic guanidino amino acids
Author: Hill, Steven
ISNI:       0000 0004 2734 8330
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2012
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Small molecules, such as oligopeptides can interact with nucleic acid targets and subsequently stimulate or supress biological functions. The purpose of this thesis was to produce nucleic acid targeting oligopeptides which contain non-natural amino acids as part of their sequence. Certain amino acids display selectivity for certain nucleobases. Arginine has a high propensity for being present at the binding interface of both protein-DNA and protein-RNA complexes. This thesis was aimed at the synthesis of two arginine analogues in which the guanidino side chain was locked in a bicyclic framework. It was expected that this would result in highly directional H-bonding capabilities of the side chains of the two analogues, which was predicted to give superior selectivity when discriminating between targets. This thesis discusses the synthetic routes undertaken in an attempt to produce these two analogues. The synthesis of the two analogues proceeded by quite different routes. The first entailed manipulation of a chiral starting material to ultimately produce the bicyclic guanidine. However, incorporation of the amino acid moiety proved difficult and thus is incomplete. However, there is scope for further work to build on the endeavours mentioned in this work. The attempted synthesis of the second analogue focused on the formation of a substituted triamine prior to cyclisation to give the bicyclic guanidine. This method also produced many problems and so the synthesis still requires further work. The thesis also details the design and synthesis of a peptide library with the majority of peptides possessing at least one arginine residue within their sequence. This produced a range of peptides in small quantities (nanomolar) which was screened against an enzyme-linked immunosorbent assay (ELISA). The results of the assay highlighted library members who displayed a binding affinity towards the oligonucleotide targets and from this their sequences were determined. Future work can be performed using these results so that binding association constants can be determined. Once the arginine analogues have been successfully synthesised these can be incorporated into these peptide sequences in place of the arginine residues.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QD Chemistry