title: Synthesis and preliminary evaluation of pro-RNA 2'-O-masked with biolabile pivaloyloxymethyl groups in an RNA interference assay.
abstract: The cellular delivery of bioactive nucleic acid-based drugs such as small interfering RNA (siRNA) represents a major technical hurdle for their pharmaceutical application. Prodrug-like approaches provide an attractive concept to address the delivery problem. With the aim to prepare RNA-based prodrugs bearing biolabile protections which facilitate cellular uptake and are prone to be removed enzymatically inside cells in order to release functional RNA, we synthesized pro-RNA totally or partially masked in 2'-OH position with pivaloyloxymethyl (PivOM) groups. A suitable strategy has been developed to synthesize and to purify base-sensitive mixed 2'-OH/2'-O-PivOM oligoribonucleotides, and to include them in siRNA. In this strategy, the fluoride labile [(triisopropylsilyl)oxy]-benzyloxycarbonyl group (tboc) as nucleobase protection (for A and C), the TBS group as 2'-OH protection and the Q-linker to solid-support were compatible with the PivOM groups masking some 2'-OH. We have taken advantage of the specific stability of the PivOM group to apply selected acidic, basic, and fluoride ions treatment for the deprotection and release of pro-RNA. This kind of pro-siRNA was studied in a human cell culture-based RNAi assay and preliminary promising data are discussed.
authors: IBMM, UMR 5247 CNRS-UM1-UM2, Université Montpellier 2, Montpellier, France.
authors: Thomas
authors: T
authors: Lavergne
authors: Carine
authors: C
authors: Baraguey
authors: Christelle
authors: C
authors: Dupouy
authors: Nora
authors: N
authors: Parey
authors: Winfried
authors: W
authors: Wuensche
authors: Georg
authors: G
authors: Sczakiel
authors: Jean-Jacques
authors: JJ
authors: Vasseur
authors: Françoise
authors: F
authors: Debart