Synthesis and antiviral evaluation of α-l-2′-deoxythreofuranosyl nucleosides

The synthesis of a series of α-l-2′-deoxythreofuranosyl nucleosides featuring the nucleobases A, T, C and U is described in seven steps from 1,2-O-isopropyledene-α-l-threose, involving a Vorbrüggen coupling and a Barton-McCombie deoxygenation protocol as the key steps. All analogues, including a phosphoramidate nucleoside phosphate prodrug of the T analogue, were evaluated against a broad panel of different viruses but found inactive, while also lacking notable cellular toxicity. The thymidine analogue showed inhibition to mitochondrial thymidine kinase-2 (TK-2), herpes simplex virus type 1 (HSV-1) TK, varicella-zoster virus (VZV) TK and Mycobacterium tuberculosis thymidylate kinase.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Practical synthesis of new series of α-l-2′-deoxythreofuranosyl nucleosides. ► These nucleosides are devoid of significant antiviral activity/cytotoxicity. ► A phosphoramidate nucleoside phosphate prodrug does not restore activity. ► Thymine analogue inhibits different thymidine kinases.