title: 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.
abstract: 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.
authors.affiliation: IBMM, UMR 5247 CNRS-UM1-UM2, Department of Nucleic Acids, Montpellier University, Place E. Bataillon, 34095 Montpellier cedex 05 (France).
authors.forename: Annabelle
authors.initials: A
authors.lastname: Biscans
authors.forename: Maxence
authors.initials: M
authors.lastname: Bos
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Martin
authors.forename: Nicholas
authors.initials: N
authors.lastname: Ader
authors.forename: Georg
authors.initials: G
authors.lastname: Sczakiel
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Vasseur
authors.forename: Christelle
authors.initials: C
authors.lastname: Dupouy
authors.forename: Françoise
authors.initials: F
authors.lastname: Debart
mesh_terms: D001483:Base Sequence; D020868:Gene Silencing; D008745:Methylation; D009843:Oligoribonucleotides / Q000138:chemical synthesis / Q000737:chemistry*; D011355:Prodrugs / Q000378:metabolism; D012313:RNA / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D009843:Oligoribonucleotides; D011355:Prodrugs; D012313:RNA
keywords: RNA; acetalesters; base-labile protecting groups; oligonucleotides; pivaloyloxylmethyl; protecting groups