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Direct Synthesis of Partially Modified 2′‐ O ‐Pivaloyloxymethyl RNAs by a Base‐Labile Protecting Group Strategy and their Potential for Prodrug‐Based Gene‐Silencing Applications
Author(s) -
Biscans Annabelle,
Bos Maxence,
Martin Anthony R.,
Ader Nicholas,
Sczakiel Georg,
Vasseur JeanJacques,
Dupouy Christelle,
Debart Françoise
Publication year - 2014
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201402382
Subject(s) - protecting group , chemistry , nuclease , nucleobase , linker , combinatorial chemistry , prodrug , rna , stereochemistry , dna , biochemistry , gene , organic chemistry , alkyl , computer science , operating system
An original and straightforward synthesis of partially modified 2′‐ O ‐pivaloyloxymethyl‐substituted (PivOM‐substituted) oligoribonucleotides has been achieved. The aim of this 2′‐enzymolabile modification was to enhance nuclease stability of RNA and transmembrane transport. To make these modified RNAs easily available we developed a base‐labile protecting group strategy with standard protections for nucleobases (acyl) and phosphates (cyanoethyl), a Q‐linker and two different acetalester protection groups for 2′‐OH: propionyloxymethyl (PrOM) and PivOM. Interestingly, orthogonal deprotection conditions based on anhydrous butylamine in THF were found to remove propionyloxymethyl groups selectively, while preserving PivOM groups. Duplex stability, circular dichroism studies and nuclease resistance, as well as the ability to inhibit gene expression of modified 2′‐ O ‐PivOM RNA, were evaluated.