Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.584007
Title: Design, synthesis and biological evaluation of novel nucleotide prodrugs as potential anti hepatitis C virus agents
Author: Perrone, Plinio
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2007
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Abstract:
Hepatitis C virus HCV represents the leading cause of liver disease. Most of the patented potential anti-HCV agents are nucleosides. Usually, to be active, nucleosides need to be phosphorylated three times in order to generate the corresponding 5'-triphosphate inside cells. Our group has developed the phosphoramidate approach that bypasses the first phosphorylation step and releases the 5'-monophosphate intracellulary. Part of the presented work was focused on the synthesis and the biological evaluation of phosphoramidates of novel 4'-modifed nucleosides AZC, AZU, AZA, dipentanoyl-AZC and ETU. Phosphoramidates with different natural L-alanine, L-valine, glycine, L-leucine, L-isoleucine, L-methionine, L-proline, L-valine and L-phenylalanine and unnatural cyclopentylglycine, dimethylglycine, /-alanine, N-methylglycine, L-ethylaspartate and D-alanine amino acid were synthesised. Octyl, dodecyl never synthesised before , methyl, ethyl, isopropyl, benzyl, 2-butyl, butyl and terf-butyl are all the variation on the ester part of the phosphoramidate structures synthesised. a- and /S-naphthyl, 8-quinoline and different substituents on the phenyl ring para-chloro, 3,4-dichloro, para-methyl and ara-methoxy are the major examples of aryl moiety variations applied to these nucleosides. The protection of the 2'- and 3'-positions with cyclopentylidene and subsequent deprotection significantly increased the overall yield of these reactions. The optimisation of the synthesis of AZA was achieved and it represents the first example of a 4'-modified ribo-purine nucleoside active against HCV. The application of our technology to AZA and AZU converted an inactive nucleoside into a sub-micromolar active phosphoramidate. The separation of the two diastereoisomers was achieved for some of the AZC phosphoramidates synthesised. A series of novel phosphoramidates of 2'-methyl modified purine adenosine and guanosine were synthesised using the 2'-, 3'-protection previously optimised. The aryl moiety a-naphthyl and phenyl and ester methyl, ethyl, /erf-butyl, benzyl variations were explored using L-alanine as amino acid. A general enhancement of activity was observed applying the phosphoramidate technology to these nucleosides.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.584007  DOI: Not available
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