Application of Phosphoramidate ProTide Technology for the Synthesis of 5’-mRNA Cap Analogs Modified on the Exocyclic Amine Group |
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Authors: | Izabela Siekierska Dr Maciej Lukaszewicz Dr Remigiusz Worch Prof Marzena Jankowska-Anyszka Dr Karolina Piecyk |
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Affiliation: | 1. Faculty of Chemistry, University of Warsaw, 1 Pasteur St., 02-093 Warsaw, Poland;2. Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, 02-089 Warsaw, Poland;3. Nencki Institute of Experimental Biology, 3 Pasteur Street, 02-093 Warsaw, Poland |
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Abstract: | Aryloxy triester phosphoramidate methodology, commonly known as ProTide technology, is one of the most widely used prodrug approaches applied to therapeutic nucleosides. This approach has been used extensively by the pharmaceutical industry and researchers in medicinal chemistry. Herein we report our adaptation of this effective method for the synthesis of bioactive 5’-mRNA cap analogues as inhibitors for targeting cap-dependent translation. The synthesis was performed in two main stages: preparation of N2-modified guanosine analogues and their subsequent transformation into prodrugs using phenylethoxy-l -alaninyl phosphorochloridate. The prepared pro-nucleotide cap analogues were tested for their capacity in enzymatic activation, inhibitory properties in a rabbit reticulocyte lysate system, and passive membrane translocation properties. |
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Keywords: | mRNA cap analogs phosphoramidate (ProTide) approach N2-guanosine modification |
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