Guinan, M, Huang, N, Smith, M and Miller, GJ (2022) Design, chemical synthesis and antiviral evaluation of 2'-deoxy-2'-fluoro-2'-C-methyl-4'-thionucleosides. Bioorganic & Medicinal Chemistry Letters, 61. 128605 - ?. ISSN 0960-894X

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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-β-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.

Item Type: Article
Additional Information: The final version of this article and all relevant information related to it, including copyrights, can be found on the publisher website at; 10.1016/j.bmcl.2022.128605
Uncontrolled Keywords: Nucleoside analogue; Thionucleoside; Antiviral; Sofosbuvir; Chemical synthesis
Subjects: Q Science > QD Chemistry
Q Science > QD Chemistry > QD415 Biochemistry
Divisions: Faculty of Natural Sciences > School of Chemical and Physical Sciences
Related URLs:
Depositing User: Symplectic
Date Deposited: 17 Mar 2022 15:28
Last Modified: 10 Jun 2022 08:34

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