Synthesis of the new nucleoside 5′-alpha-iminophosphates using Staudinger reaction

• Published in: Bioorganic chemistry 2022-10, Vol.127, p.105987-105987, Article 105987
• Main Authors: Vasilyeva, Svetlana V., Kuznetsova, Alexandra A., Baranovskaya, Elizaveta E., Kuznetsov, Nikita A., Lomzov, Alexander A., Pyshnyi, Dmitrii V.
• Format: Article
• Language: English
• Subjects: Alpha-phosphate mimetic nucleotides; Nucleoside 5′-α-iminophosphates; Staudinger reaction; Terminal deoxynucleotidyl transferase substrate
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2022.105987

[Display omitted] •New compounds - nucleoside 5′-α-iminophosphates were obtained using Staudinger reaction.•It is alpha-phosphate mimetic nucleotide in which an oxygen atom is replaced by a imino (=N-R)-group.•Nucleoside 5′-alpha-iminophosphates unlike relevant amidates are resonance-stabilized, insensitive to hydrolysis.•Thimidine 5′-α-DMI-iminotriphosphate can serve as substrate for human terminal deoxynucleotidyltransferase TdT. Efficient protocols were developed for the synthesis of a new compounds - nucleoside 5′-α-iminophosphates using the Staudinger reaction. These substances are alpha-phosphate mimetic nucleotide in which an oxygen atom is replaced by a corresponding imino (=N-R)-group. Various 5′-iminomonophosphates of nucleosides were obtained. A chemical method for the synthesis of triphosphate derivatives based on the iminomonophosphates has been designed. Thymidine 5′-(1,3-dimethylimidazolidin-2-ylidene)-triphosphate (ppp(DMI)T) was synthesized, its hydrolytic stability and substrate properties in relation to some DNA polymerases was firstly studied. It was shown that ppp(DMI)T can serve as substrate for enzyme catalyzed template-independent DNA synthesis by human terminal deoxynucleotidyltransferase TdT.