Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.771139
Title: The modification of nucleosides to probe decarboxylation and denitration processes
Author: Williams, Kathryn Rose
ISNI:       0000 0004 7656 753X
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2018
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Abstract:
The work presented in this thesis explored the modification of naturally occurring nucleosides and is split into two main sections investigating the processes of denitration and decarboxylation. A common theme of the work investigated the nitration of nucleosides and their biological role. Both purines and pyrimidine nucleosides have been investigated, with the initial focus being on guanosine and a potential repair mechanism of a common DNA lesion associated with nitration. Secondly, an essential decarboxylation step in the biosynthesis of pyrimidine nucleosides was investigated to probe whether formation of bioisosteric analogues of a key intermediate in this process could aid in the treatment of disease. 8-Nitroguanine is a DNA lesion strongly associated with inflammation-related carcinogenesis. Nitration of the guanine base greatly labilises the glycosidic bond, often resulting in the formation of abasic sites which can lead to mispairing during DNA replication. A potential repair mechanism of the lesion was investigated involving a reductive denitration reaction. Synthesis of the ribonucleoside form of 8-nitroguanosine was achieved and the process of reductive denitration was investigated using sodium borohydride. The main product of the reduction was found to be 8-aminoguanosine, but a small amount of guanosine was found to form showing reductive denitration of the lesion is a chemically feasible reaction and thus a potential repair mechanism. A deuterium labelling study proved the origin of the guanosine formed was from the 8-nitroguanosine starting material. The final step in the de novo biosynthesis of pyrimidine nucleotides involves a decarboxylation reaction to produce uridine 5'-monophosphate, catalysed by the enzyme orotidine monophosphate decarboxylase (ODCase). Certain disease causing organisms, such as the malaria parasite, rely on this pathway to obtain the pyrimidines they require. Humans utilise two pathways to obtain pyrimidines which introduces the possibility of inhibiting the de novo pathway as a means of therapeutic intervention. A series of eleven bioisosteric analogues of the natural substrate of ODCase were synthesised as potential inhibitors of the enzyme and antimalarial agents. Computational docking of the eleven compounds into a crystal structure of ODCase was carried out and showed that all are predicted to fit into the active site. All eleven compounds synthesised have been sent for biological testing in a 3D7 assay to assess their antimalarial activity.
Supervisor: Cosstick, Rick ; O'Neil, Ian Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.771139  DOI:
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