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

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Salihovic, Admir and Ascham, Alex and Taladriz-Sender, Andrea and Bryson, Samantha and Withers, Jamie M. and Mckean, Iain J. W. and Hoskisson, Paul A. and Grogan, Gideon and Burley, Glenn A. (2024) Gram-scale enzymatic synthesis of 2′-deoxyribonucleoside analogues using nucleoside transglycosylase-2. Chemical Science, 15 (37). pp. 15399-15407. ISSN 2041-6539 (https://doi.org/10.1039/D4SC04938A)

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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.

ORCID iDs

Salihovic, Admir, Ascham, Alex, Taladriz-Sender, Andrea ORCID logoORCID: https://orcid.org/0000-0002-8274-4761, Bryson, Samantha, Withers, Jamie M. ORCID logoORCID: https://orcid.org/0000-0002-9746-9467, Mckean, Iain J. W. ORCID logoORCID: https://orcid.org/0000-0002-4970-1508, Hoskisson, Paul A. ORCID logoORCID: https://orcid.org/0000-0003-4332-1640, Grogan, Gideon and Burley, Glenn A.;
CORE (COnnecting REpositories)