Design, synthesis and biological evaluation of novel nucleotide prodrugs as potential anti hepatitis C virus agents.

Perrone, Plinio. 2007. Design, synthesis and biological evaluation of novel nucleotide prodrugs as potential anti hepatitis C virus agents. PhD Thesis, Cardiff University.

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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, b-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 b-naphthyl, 8-quinoline and different substituents on the phenyl ring (para-chloro, 3,4-dichloro, para-methyl and para-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.

Item Type:	Thesis (PhD)
Status:	Unpublished
Schools:	Pharmacy
Subjects:	R Medicine > RM Therapeutics. Pharmacology
ISBN:	9781303176845
Funders:	Roche Biosciences in Palo Alto (San Francisco)
Date of First Compliant Deposit:	30 March 2016
Last Modified:	12 Feb 2016 23:12
URI:	https://orca.cardiff.ac.uk/id/eprint/54327

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