Synthesis and Preliminary Evaluation of pro-RNA 2'-O-Masked with Biolabile Pivaloyloxymethyl Groups in an RNA Interference Assay

Thomas Lavergne (1) , Carine Baraguey (1) , Christelle Dupouy (1) , N. Parey (1) , Winfried Wuensche (2) , Georg Sczakiel (2) , Jean-Jacques Vasseur (1) , Françoise Debart (1)

1 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]
2 Institut für Molekulare Medizin

The cellular delivery of bioactive nucleic acidbased 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 aimto 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 20 -OH position with pivaloyloxymethyl (PivOM) groups. A suitable strategy has been developed to synthesize and to purify base-sensitive mixed 20 -OH/20 -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 20 -OH protection and the Q-linker to solid-support were compatible with the PivOM groups masking some 20 -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.

Domaines: Chimie organique

Thomas Lavergne, Carine Baraguey, Christelle Dupouy, N. Parey, Winfried Wuensche, et al.. Synthesis and Preliminary Evaluation of pro-RNA 2'-O-Masked with Biolabile Pivaloyloxymethyl Groups in an RNA Interference Assay. Journal of Organic Chemistry, 2011, 76, pp.5719-5731. ⟨10.1021/jo200826h⟩. ⟨hal-00616629⟩