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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. 2014

Annabelle Biscans, and Maxence Bos, and Anthony R Martin, and Nicholas Ader, and Georg Sczakiel, and Jean-Jacques Vasseur, and Christelle Dupouy, and Françoise Debart
IBMM, UMR 5247 CNRS-UM1-UM2, Department of Nucleic Acids, Montpellier University, Place E. Bataillon, 34095 Montpellier cedex 05 (France).

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.

UI MeSH Term Description Entries
D008745 Methylation Addition of methyl groups. In histo-chemistry methylation is used to esterify carboxyl groups and remove sulfate groups by treating tissue sections with hot methanol in the presence of hydrochloric acid. (From Stedman, 25th ed) Methylations
D009843 Oligoribonucleotides A group of ribonucleotides (up to 12) in which the phosphate residues of each ribonucleotide act as bridges in forming diester linkages between the ribose moieties.
D011355 Prodrugs A compound that, on administration, must undergo chemical conversion by metabolic processes before becoming the pharmacologically active drug for which it is a prodrug. Drug Precursor,Drug Precursors,Pro-Drug,Prodrug,Pro-Drugs,Precursor, Drug,Precursors, Drug,Pro Drug,Pro Drugs
D001483 Base Sequence The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence. DNA Sequence,Nucleotide Sequence,RNA Sequence,DNA Sequences,Base Sequences,Nucleotide Sequences,RNA Sequences,Sequence, Base,Sequence, DNA,Sequence, Nucleotide,Sequence, RNA,Sequences, Base,Sequences, DNA,Sequences, Nucleotide,Sequences, RNA
D012313 RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. (Rieger et al., Glossary of Genetics: Classical and Molecular, 5th ed) RNA, Non-Polyadenylated,Ribonucleic Acid,Gene Products, RNA,Non-Polyadenylated RNA,Acid, Ribonucleic,Non Polyadenylated RNA,RNA Gene Products,RNA, Non Polyadenylated
D020868 Gene Silencing Interruption or suppression of the expression of a gene at transcriptional or translational levels. Gene Inactivation,Inactivation, Gene,Silencing, Gene

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