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The design and synthesis of novel anti-viral agents

Celiker, I. (2017) The design and synthesis of novel anti-viral agents. PhD thesis, University of Reading

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Abstract/Summary

Viral infections account for 25.4% of all human illnesses. Current anti-viral nucleosides are able to prevent viral replication; however, viruses evolve resistance to available treatments. Ribose nucleosides are ubiquitous; however due to the discriminatory nature of kinases, low intracellular concentrations of the active triphosphate is a significant factor in inactivity. In contrast, oxetane nucleosides have been shown to be phosphorylated by these kinases with high levels of the required active nucleotide triphosphate (NTP) resulting. Oxetane nucleosides, however, have been found to be inactivated by pyrimidine nucleoside phosphorylases (PNPs). Previous studies have illustrated that sulfur containing nucleosides are not hydrolysed by PNPs. Therefore in this programme a library of 9 novel 3,3-bis(hydroxymethyl)-thietan-2-yl nucleosides was synthesised using Vorbrüggen conditions starting from a fluorothietane precursor, over 8 steps. Cell viability studies using an XTT assay on the thymine (103% ± 4.9%), uracil (95% ± 2.3%), 5- fluorouracil (98% ± 7.5%) and 5,6-dimethyl uracil (82% ± 4.1%) derivatives showed no significant loss in cell viability at up to 100 μM concentration, suggesting they were suitable for further study in anti-viral screens. Steps towards the synthesis of a complementary library of 4,4-bis(hydroxymethyl)-thietan-2-yl nucleosides have been optimised with successful synthesis of a novel key intermediate, thietane-2-one, in a yield of 37% over 6 steps. 4’-Thiohamamelose nucleosides show promise as potential anti-viral compounds as previous studies have shown that 4’-thioribose nucleosides are stable to PNPs and have longer half-lives than ribose nucleosides. Increasing the stability of the 4’-thiohamamelose nucleosides could improve the potential for development of the anti-viral profiles of this class of compounds. Therefore the chemistry of 4’-thiohamamelose nucleosides has been explored, with an intermediate hamamelolactone being prepared in a yield of 44% over 5 steps. Small molecule nucleosides offer the greatest benefits as anti-viral compounds versus other small molecule anti-viral agents as nucleosides are able to directly halt viral replication. The sulfur containing nucleosides are potentially more stable than their ribose counterparts, leading to better pharmacological and pharmacodynamics outcomes.

Item Type:Thesis (PhD)
Thesis Supervisor:Osborn, H. and Greenland, B.
Thesis/Report Department:School of Chemistry, Food and Pharmacy
Identification Number/DOI:
Divisions:Faculty of Life Sciences > School of Chemistry, Food and Pharmacy
ID Code:72588
Date on Title Page:2016

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