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Design, chemical synthesis and antiviral evaluation of 2'-deoxy-2'-fluoro-2'-C-methyl-4'-thionucleosides.

Guinan, Mieke; Huang, Ningwu; Smith, Mark; Miller, Gavin

Authors

Mieke Guinan

Ningwu Huang

Mark Smith



Abstract

Nucleoside analogues represent an historically accomplished class of antiviral drug. Notwithstanding this, new molecular scaffolds are required to overcome their limitations and evolve pharmacophore space within this established field. Herein, we develop concise synthetic access to a new 2'-deoxy-2'-fluoro-2'-C-methyl-4'-thionucleoside chemotype, including the ProTide form of the uridine analogue. Biological evaluation of these materials in the Hepatitis C replicon assay shows little activity for the canonical pyrimidine forms, but the phosphoramidate of 2'-deoxy-2'-fluoro-2'-C-methyl-ß-d-4'-thiouridine has an EC50 of 2.99 µM. Direct comparison to the established Hepatitis C drug Sofosbuvir shows a 100-fold drop in activity upon substituting the furanose chalcogen; the reasons for this are as yet unclear.

Journal Article Type Article
Acceptance Date Jan 30, 2022
Online Publication Date Feb 2, 2022
Publication Date Apr 1, 2022
Publicly Available Date Mar 28, 2024
Journal Bioorganic & Medicinal Chemistry Letters
Print ISSN 0960-894X
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 61
Article Number 128605
DOI https://doi.org/10.1016/j.bmcl.2022.128605
Keywords Nucleoside analogue; Thionucleoside; Antiviral; Sofosbuvir; Chemical synthesis
Publisher URL https://www.sciencedirect.com/science/article/pii/S0960894X22000816?via%3Dihub