title: The biolabile 2'-O-pivaloyloxymethyl modification in an RNA helix: an NMR solution structure.
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.
authors: IBMM UMR 5742 CNRS-UM1-UM2 Université Montpellier II, Place Eugene Bataillon, 34095 Montpellier Cedex 05, France. carine.baraguey@univ-montp2.fr
authors: Carine
authors: C
authors: Baraguey
authors: Eveline
authors: E
authors: Lescrinier
authors: Thomas
authors: T
authors: Lavergne
authors: Françoise
authors: F
authors: Debart
authors: Piet
authors: P
authors: Herdewijn
authors: Jean-Jacques
authors: JJ
authors: Vasseur
mesh_terms: D001483:Base Sequence; D008745:Methylation; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D009690:Nucleic Acid Conformation; D011355:Prodrugs / Q000737:chemistry*; D012313:RNA / Q000737:chemistry*; D020871:RNA Stability; D012266:Ribose / Q000737:chemistry*
chemical_list: D011355:Prodrugs; D012313:RNA; D012266:Ribose