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

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

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.

Citation

Guinan, M., Huang, N., Smith, M., & Miller, G. (2022). Design, chemical synthesis and antiviral evaluation of 2'-deoxy-2'-fluoro-2'-C-methyl-4'-thionucleosides. Bioorganic and Medicinal Chemistry Letters, 61, Article 128605. https://doi.org/10.1016/j.bmcl.2022.128605

• Journal Article Type: Article
• Acceptance Date: Jan 30, 2022
• Online Publication Date: Feb 2, 2022
• Publication Date: Apr 1, 2022
• Publicly Available Date: Feb 3, 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