Gram-scale enzymatic synthesis of 2′-deoxyribonucleoside analogues using nucleoside transglycosylase-2

Admir Salihovic, Alex Ascham, Andrea Taladriz-Sender, Samantha Bryson, Jamie M. Withers, Iain J. W. Mckean, Paul A. Hoskisson, Gideon Grogan*, Glenn A. Burley*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Abstract

Nucleosides are pervasive building blocks that are found throughout nature and used extensively in medicinal chemistry and biotechnology. However, the preparation of base-modified analogues using conventional synthetic methodology poses challenges in scale-up and purification. In this work, an integrated approach involving structural analysis, screening and reaction optimization, is established to prepare 2′-deoxyribonucleoside analogues catalysed by the type II nucleoside 2′-deoxyribosyltransferase from Lactobacillus leichmannii (LlNDT-2). Structural analysis in combination with substrate profiling, identified the constraints on pyrimidine and purine acceptor bases by LlNDT2. A solvent screen identifies pure water as a suitable solvent for the preparation of high value purine and pyrimidine 2′-deoxyribonucleoside analogues on a gram scale under optimized reaction conditions. This approach provides the basis to establish a convergent, step-efficient chemoenzymatic platform for the preparation of high value 2′-deoxyribonucleosides.
Original languageEnglish
Pages (from-to)15399-15407
Number of pages9
JournalChemical Science
Volume15
Issue number37
Early online date27 Aug 2024
DOIs
Publication statusPublished - 7 Oct 2024

Keywords

  • nucleosides
  • base-modified analogues
  • 2′-deoxyribonucleosides

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