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Design, synthesis, and biological evaluation of novel nucleotide prodrugs as potential therapeutics

Alanazi, Ashwag 2020. Design, synthesis, and biological evaluation of novel nucleotide prodrugs as potential therapeutics. PhD Thesis, Cardiff University.
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Cancer and viral infections such as hepatitis B infection and acquired immune deficiency syndrome (AIDS) have caused millions of deaths worldwide. The use of nucleoside analogues, a main class of treatment for these diseases, is limited due to their unpleasant side effects and the development of resistance. Hence, there is an urgent need for new and effective anticancer agents and antiviral agents for treating these diseases. These limitations of nucleotide analogues can be improved by delivering them into cells as monophosphate prodrugs rather than as nucleosides. The aryloxy triester phosphoramidate prodrug technology, commonly referred to as ProTide technology, is one of the most successful prodrug technologies used to enhance the drug-like properties of therapeutic nucleosides. However, a key issue is that ProTide metabolism depends on the expression of two different enzymes at the action site. Additionally, due to the system regarding patenting and intellectual property, its extensive use by the pharmaceutical industry and medicinal chemistry academic researchers for the discovery of nucleoside analogue ProTides has limited further applications. Therefore, a new IP-free nucleotide prodrug technology is needed to stimulate the discovery of new anticancer and antiviral nucleoside and nucleotide prodrugs. The aim of this study was to discover new IP-free nucleoside monophosphate prodrugs that can treat cancer, HBV, and HIV and overcome current resistance mechanisms. Particularly, we aimed to design a new IP-free monophosphate prodrug approach, which was termed POMtide and POCtide prodrugs. The POMtide monophosphate group is masked by pivaloyloxymethyl (POM) and aryl motifs, while the POCtide monophosphate group is masked by isopropyloxymethylcarbonate (POC) and aryl motifs. The nucleoside analogue prodruges synthesised in this study include d4T, FUDR, AraC, L-thymidine, L-uridine, and lamivudine as well as their derivatives. Metabolism studies of these prodrugs are reported for the release of desired metabolites, and for the first time, the POMtide metabolism pathway is reported. Additionally, these prodrugs show good stability in human serum, and their biological evaluation is reported against several established tumour cell lines. Collectively, the data indicated that the potency of the anticancer POMtide prodrugs was comparable to that of anticancer ProTides drugs, and in some cases, it was much better. Hence, they could be considered potential therapeutics.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Pharmacy
Subjects: Q Science > Q Science (General)
Date of First Compliant Deposit: 11 August 2020
Last Modified: 25 Jun 2021 14:18

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