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Design, synthesis and biological evaluation of novel bioactive nucleosides and nucleotides

Derudas, Marco 2009. Design, synthesis and biological evaluation of novel bioactive nucleosides and nucleotides. PhD Thesis, Cardiff University.

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At the present there are 36 approved antiviral drugs in the UK of which half are nucleoside analogues. However, the emergence of drug resistance and of new virus strains necessitates new drugs. In particular in this thesis, different nucleoside analogues were studied as potential antivirals. One of the major issues related to nucleoside analogues is the emergence of resistance due to a lack of bioactivation to the monophosphate form. To overcome this issue, the phosphoramidate ProTide technology can be applied. This strategy allows the delivery of the monophosphate form directly inside the cell. Bicyclic nucleoside analogues are a new class of anti-varicella zoster agents of which Cfl743 is the most potent anti-varicella zoster compounds reported to date. Its 5'-valyl derivative, FV100, is currently in phase II clinical trials. A series of derivatives to increase the activity and to investigate the mechanism of action of this new class of compound are reported. Moreover, attempts to improve the scale up synthesis of FV100 are described. Ribavirin is a broad spectrum antiviral drug. The application of the ProTide approach to this compound was not successful. Enzymatic and molecular modelling studies have been performed in order to understand the lack of activity. Acyclovir and its esters are currently the treatment of choice for herpes simplex and varicella-zoster infections. The application of the ProTide technology gave surprising results. In fact, these compounds have been found to be active against HIV, whilst ACV itself did not show any activity. Moreover, these compounds retained activity versus thymidine kinase deficient strains against which acyclovir lost activity. These striking results prompted us to investigate other different nucleoside analogues, through a virtual screening using reverse transcriptase, guanylate or adenylate kinase and human polymerase y. The selected nucleoside analogues from this study include: ganciclovir, penciclovir and their derivatives. ProTides of these are thus pursued.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Pharmacy
ISBN: 9781303189531
Date of First Compliant Deposit: 30 March 2016
Last Modified: 16 Oct 2014 13:08

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