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

Bioorg Med Chem Lett. 2022 Apr 1:61:128605. doi: 10.1016/j.bmcl.2022.128605.

Mieke Guinan ¹, Ningwu Huang ², Mark Smith ², Gavin J Miller ³

Affiliations

1 Lennard-Jones Laboratory, School of Chemical and Physical Sciences, Keele University, Keele, Staffordshire, ST5 5BG, United Kingdom; Centre for Glycoscience Research, Keele University, Keele, Staffordshire, ST5 5BG, United Kingdom.
2 Riboscience LLC, 428 Oakmead Pkwy, Sunnyvale, CA 94085, USA.
3 Lennard-Jones Laboratory, School of Chemical and Physical Sciences, Keele University, Keele, Staffordshire, ST5 5BG, United Kingdom; Centre for Glycoscience Research, Keele University, Keele, Staffordshire, ST5 5BG, United Kingdom. Electronic address: g.j.miller@keele.ac.uk.

PMID: 35123007 DOI: 10.1016/j.bmcl.2022.128605

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-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.

Keywords

Antiviral; Chemical synthesis; Nucleoside analogue; Sofosbuvir; Thionucleoside.

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