Study of the Staudinger Reaction and Reveal of Key Factors Affecting the Efficacy of Automatic Synthesis of Phosphoryl Guanidinic Oligonucleotide Analogs


In this work, we introduce a novel nuanced analysis of the chemical transformations occurs during the automatic synthesis of phosphoryl guanidine oligonucleotides (PGOs). It was shown on model compounds that the stable form of phosphoryl guanidine afforded by the P(III) atom of the phosphite component oxidation by the corresponding organic azide is the positively charged triester phosphoryl guanidinium fragment. The idea that the presence of such kind of fragments in PGOs, obtained under automatic DNA synthesis conditions, may have an adverse effect on its backbone stability when at the postsynthetic stage PGOs on polymer treated with aqueous basic solutions has been proposed. To overcome this impediment, we suggest before the stage of the desired PGO final deblocking to treat the solid phase with a protected PGO chain fixed with a solution of a strong base in an anhydrous medium. In consequence of this treatment, the transformation of PGO triester form to diester takes place, imparting better stability to the modified chain under deblocking conditions and increasing the yield of the desired oligonucleotide derivatives.

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The authors are grateful to the Common center for Collective Use of ICBFM of the Siberian Branch, Russian Academy of Sciences, for mass spectrometric analysis of oligonucleotides. The authors are grateful to the Chemical Research Center for Collective Use of the Siberian Branch, Russian Academy of Sciences (NIOC SB RAS), for carrying out spectral and analytical measurements.


This work was supported by the Russian Science Foundation, grant no. 18-14-00357. The experiments on optimizing the scheme of mass-spectrometric analysis of nucleotide derivatives are carried out in the framework of basic budget financing, project no. 0309-2016-0004. Quantum-mechanical calculations are carried out with the support of the Ministry of Science and Higher Education of the Russian Federation, grant no. 14.W03.31.0034.

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Correspondence to D. V. Pyshnyi.

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The authors declare no conflict of interest.

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Translated by Sh. Galyaltdinov

Abbreviations: PGO, phosphoryl guanidine oligonucleotide; ADMP, 2-azido-1,3-dimethylimidazolinium hexafluorophosphate; dT, thymidine; ETT, 5-(ethylthio)-1H-tetrazole.

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Bazhenov, M.A., Shernyukov, A.V., Kupryushkin, M.S. et al. Study of the Staudinger Reaction and Reveal of Key Factors Affecting the Efficacy of Automatic Synthesis of Phosphoryl Guanidinic Oligonucleotide Analogs. Russ J Bioorg Chem 45, 699–708 (2019) doi:10.1134/S1068162019060074

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  • automated oligonucleotide synthesis
  • modified oligonucleotides
  • organic azides
  • phosphoazides
  • phosphoryl guanidine oligonucleotides (PGO)
  • phosphoryl guanidines
  • Staudinger reaction