Biocatalytic Nucleobase Diversification of 4'-Thionucleosides and Application of Derived 5-Ethynyl-4'-thiouridine for RNA synthesis detection.

Westarp, Sarah; Benckendorff, Caecilie; Motter, Jonas; Rohrs, Viola; Sanghvi, Yogesh; Neubauer, Peter; Kurreck, Jens; Kurreck, Anke; Miller, Gavin J

Abstract

Nucleoside and nucleotide analogues have proven to be transformative in the treatment of viral infections and cancer. One branch of structural modification to deliver new nucleoside analogue classes explores replacement of canonical ribose oxygen with a sulfur atom. Whilst biological activity of such analogues has been shown in some cases, widespread exploration of this compound class is hitherto hampered by the lack of a straightforward and universal nucleobase diversification strategy. Herein, we present a synergistic platform enabling both biocatalytic nucleobase diversification from 4'-thiouridine in a one-pot process, and chemical functionalization to access new entities. This methodology delivers entry across pyrimidine and purine 4'-thionucleosides, paving a way for wider synthetic and biological exploration. We exemplify our approach by enzymatic synthesis of 5-iodo-4'-thiouridine on multi-milligram scale and from here switch to complete chemical synthesis of a novel nucleoside analogue probe, 5-ethynyl-4'-thiouridine. Finally, we demonstrate the utility of this probe to monitor RNA synthesis in proliferating HeLa cells, validating its capability as a new metabolic RNA labelling tool. [Abstract copyright: © 2024 Wiley‐VCH GmbH.]

Citation

Westarp, S., Benckendorff, C., Motter, J., Rohrs, V., Sanghvi, Y., Neubauer, P., …Miller, G. J. (in press). Biocatalytic Nucleobase Diversification of 4'-Thionucleosides and Application of Derived 5-Ethynyl-4'-thiouridine for RNA synthesis detection. Angewandte Chemie, Article e202405040. https://doi.org/10.1002/anie.202405040

• Journal Article Type: Article
• Acceptance Date: May 23, 2024
• Online Publication Date: May 24, 2024
• Deposit Date: Jun 10, 2024
• Journal: Angewandte Chemie (International ed. in English)
• Print ISSN: 0044-8249
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Article Number: e202405040
• DOI: https://doi.org/10.1002/anie.202405040
• Keywords: Nucleoside analogues Biocatalysis Nucleoside phosphorylase Sulfur Metabolic Probes
• Public URL: https://keele-repository.worktribe.com/output/847385
• Publisher URL: https://onlinelibrary.wiley.com/doi/10.1002/anie.202405040