Scalable Synthesis and Biological Evaluation of 3′-Deoxy-3′,4′-didehydronucleoside Triphosphates

The Journal of Organic Chemistry 2026

View at publisher
Authors: James M. Wood, Dan G. Torres, Roselis A. Landaeta Aponte, Sandesh Deshpande, Alice M. McSweeney, Rinu Shrestha, Andrew Reddy, Gary B. Evans, Steven C. Almo, Tyler L. Grove, Richard L. Kingston, Vernon K. Ward
+1 more Lawrence D. Harris
DOI: 10.1021/acs.joc.6c00483
Cited by: 1
References: 29

Abstract

3'-Deoxy-3',4'-didehydronucleoside triphosphates (ddhNTPs) are antiviral metabolites produced by viperin and viperin-like enzymes, all of which are members of the radical SAM superfamily of enzymes. To date, synthetic access to ddhUTP, ddhGTP, and ddhATP has remained limited. We report a scalable synthesis of the complete ddhN nucleoside family using Bobbitt's salt-mediated oxidation of nucleoside orthoformates, including a chromatography-free route to ddhC on a gram scale. This methodology enabled the first synthesis and evaluation of ddhUTP, ddhGTP, and ddhATP as inhibitors of RNA-dependent RNA polymerases, with ddhATP confirmed to act as an obligate chain terminator through primer extension assays.

Fields of Study & Subjects

Biochemical and Molecular Research RNA modifications and cancer interferon and immune responses

Publication details

Journal / source
The Journal of Organic Chemistry
Publisher
American Chemical Society (ACS)
Volume
91
Issue
19
Pages
6744–6750
Publication date
4 May 2026
Language
EN