Issue 16, 2013
From the journal:

Organic & Biomolecular Chemistry

The biolabile 2′-O-pivaloyloxymethyl modification in an RNA helix: an NMR solution structure†

Carine Baraguey,*a   Eveline Lescrinier,b   Thomas Lavergne,a   Françoise Debart,a   Piet Herdewijnb  and  Jean-Jacques Vasseura  

* Corresponding authors

a IBMM UMR 5742 CNRS-UM1-UM2 Université Montpellier II, Place Eugene Bataillon, 34095 Montpellier Cedex 05, France
E-mail: carine.baraguey@univ-montp2.fr
Fax: +33 4-67-04-20-29
Tel: +33 4-67-14-38-98

b Rega Institute for Medical Research, Katholeike Universiteit Leuven, Minderbroederstraat 10, 3000 Leuven, Belgium

Abstract

The pivaloyloxymethyl (PivOM) group is a biolabile 2′-O-ribose protection that is under development in a prodrug-based approach for siRNA applications. Besides an expected cellular uptake, nucleic acid sequences carrying PivOM showed also increased nuclease resistance and, in most cases, an affinity for complementary RNA. The r(CGCU*ACGC)dT:r(GCGUAGCG)dT model duplex containing a single modified residue (U*) was synthesized and its solution structure was determined by NMR. The duplex showed a maintained A-RNA helix. In U*, both 2′-O-acetal ester side chain and ring pucker presented a notable rigid conformation. The PivOM moiety was oriented with the carbonyl group turned outside the minor groove and with trans, -ac and -ac torsion angles around the C2′–O2′, O2′–CA and CA–OB1 bonds respectively. Gauche effects and dipolar interactions between the PivOM and the backbone appeared to be the predominant factors influencing the PivOM conformation and the orientation of the two supplementary H acceptors suggested that hydration could also play a role in the duplex stability.

Graphical abstract: The biolabile 2′-O-pivaloyloxymethyl modification in an RNA helix: an NMR solution structure

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Article information

DOI
https://doi.org/10.1039/C3OB27005J
Article type
Paper
Submitted
15 Oct 2012
Accepted
11 Feb 2013
First published
12 Feb 2013

Org. Biomol. Chem., 2013,11, 2638-2647

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The biolabile 2′-O-pivaloyloxymethyl modification in an RNA helix: an NMR solution structure

C. Baraguey, E. Lescrinier, T. Lavergne, F. Debart, P. Herdewijn and J. Vasseur, Org. Biomol. Chem., 2013, 11, 2638 DOI: 10.1039/C3OB27005J

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