Biological and Medicinal Chemistry

Biocatalytic Synthesis of 2-Seleno Pyrimidine Nucleosides via Transglycosylation

Abstract

Selenium-modified nucleosides are powerful tools to study the structure and function of nucleic acids and their protein interactions. The wide-spread application of 2-seleno pyrimidine nucleosides is currently limited by low yields in established synthetic routes. Here, we describe the optimization of the synthesis of 2-Se-uridine and 2-Se-thymidine derivatives by thermostable nucleoside phosphorylases in transglycosylation reactions using natural uridine or thymidine as sugar donors. Reactions were performed at 60 or 80 °C and at pH 9 under hypoxic conditions to improve the solubility and stability of the 2-Se-nucleobases in aqueous media. To optimize the conversion, the reaction equilibria in analytical transglycosylation reactions were studied. The equilibrium constants of phosphorolysis of the 2-Se-pyrimidines were between 5 and 10 and thus belong to the highest described so far. Thus, a ten-fold excess of sugar donor was needed to achieve 40-48% conversion to the target nucleoside. Scale-up of the optimized conditions provided four Se-containing nucleosides in 6-40% isolated yield which compares favorably to established chemical routes.

Content

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Supplementary material

Thumbnail image of Hellendahl_Kaspar_2020_SI_Se-nucleosides.pdf
Hellendahl Kaspar 2020 SI Se-nucleosides

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