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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

Authors

Sarah Westarp

Caecilie Benckendorff

Jonas Motter

Viola Rohrs

Yogesh Sanghvi

Peter Neubauer

Jens Kurreck

Anke Kurreck



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.

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/ange.202405040

Journal Article Type Article
Acceptance Date May 23, 2024
Online Publication Date May 24, 2024
Deposit Date Jun 10, 2024
Publicly Available Date Jun 10, 2024
Journal Angewandte Chemie
Print ISSN 0044-8249
Publisher Wiley
Peer Reviewed Peer Reviewed
Article Number e202405040
DOI https://doi.org/10.1002/ange.202405040
Public URL https://keele-repository.worktribe.com/output/847511

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Licence
https://creativecommons.org/licenses/by-nc/4.0/

Publisher Licence URL
https://creativecommons.org/licenses/by-nc/4.0/

Copyright Statement
Dieser Beitrag wurde nach Begutachtung und Überarbeitung sofort als"akzeptierter Artikel" (Accepted Article; AA) publiziert. Die deutscheÜbersetzung wird gemeinsam mit der endgültigen englischen Fassungerscheinen. Die endgültige englische Fassung (Version of Record)wird ehestmöglich nach dem Redigieren und einem Korrekturgang alsEarly-View-Beitrag erscheinen und kann sich naturgemäß von der AA-Fassung unterscheiden. Leser sollten daher die endgültige Fassung,sobald sie veröffentlicht ist, verwenden. Für die AA-Fassung trägt derAutor die alleinige Verantwortu


After review and revision, this article was immediately published as an “Accepted Article” (AA). The German translation will appear together with the final English version. The final English version (version of record) will appear as an early view article as soon as possible after editing and proofreading and may of course differ from the AA version. Readers should therefore use the final version as soon as it is published. The author bears sole responsibility for the AA version.

The final version of this article and all relevant information related to it, including copyrights, can be found on the publisher website.






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