Use of Arabinonucleosides for Development and Implementation of a Novel 2'-O-Protecting Group for Efficient Solid-Phase Synthesis and 2'-O-Deprotection of RNA Sequences

Mayumi Takahashi; Brian M. Cawrse; Andrzej GrajkowskiSerge L. Beaucage

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Use of Arabinonucleosides for Development and Implementation of a Novel 2'-O-Protecting Group for Efficient Solid-Phase Synthesis and 2'-O-Deprotection of RNA Sequences

机译：Use of Arabinonucleosides for Development and Implementation of a Novel 2'-O-Protecting Group for Efficient Solid-Phase Synthesis and 2'-O-Deprotection of RNA Sequences

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The implementation of protecting groups for 2'-hydroxyl function of ribonucleosides is very demanding in that synthetic RNA sequences must be highly pure to ensure the safety and efficacy of nucleic acid-based drugs for treatment of human diseases. A synthetic approach consisting of a condensation reaction between 2'-O-aminoribonucleosides with ethyl pyruvate has been employed to provide stable 2'-O-imino-2-methyl propanoic acid ethyl esters. Conversion of these esters to fully protected ribonucleoside phosphoramidite monomers has allowed rapid and efficient incorporation of 2'-O-protected ribonucleosides into RNA sequences while minimizing the formation of process-related impurities during solid-phase synthesis. Two chimeric 20-mer RNA sequences have been synthesized and then exposed to a solution of sodium hydroxide to saponify the 2'-O-imino-2-methyl propanoic acid ethyl ester protecting groups to their sodium salts. When subjected to ion-exchange conditions at 65°C and near neutral pH, fully deprotected RNA sequences are isolated without production of alkylating side-products and/or formation of mutagenic nucleobase adducts.

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《Current Protocols in Nucleic Acid Chemistry》 |2022年第1期|e346-1-e346-34|共34页
作者
Mayumi Takahashi; Brian M. Cawrse; Andrzej GrajkowskiSerge L. Beaucage;
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作者单位

Laboratory of Biological Chemistry, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland;

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正文语种英语
中图分类生物化学;
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2'-O-imino-2-propanoic acid ethyl ester; arabinonucleosides; intramolecular decarboxylative 2'-O-deprotection; ribonucleoside-2'-O-protecting groups; solid-phase RNA synthesis;

Use of Arabinonucleosides for Development and Implementation of a Novel 2'-O-Protecting Group for Efficient Solid-Phase Synthesis and 2'-O-Deprotection of RNA Sequences

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