Oligoribonucleotide analogues containing a mixed backbone of phosphodiester and formacetal internucleoside linkages, together with vicinal 2'-O-methyl groups.
Oligoribonucleotides containing formacetal internucleoside linkages have been prepared and studied by UV melting experiments. In RNA duplexes, the formacetal substitution is stabilizing (Deltat(m)=0 to +0.9 degrees C per modification) at physiological salt concentrations (0.1 M) but destabilizing (Deltat(m)=-0.4 to -0.8 degrees C per modification) at high salt concentrations (1 M); this suggests that reduction of electrostatic repulsion contributes substantially to the stabilization. The presence of 2'-O-Me substituents increases the stabilities of the duplexes (Deltat(m)=+0.5 to +1.1 degrees C per modification). The positive effects of formacetals and 2'-O-Me groups were independent and additive. (1)H NMR studies on monomeric model compounds containing 3'-(ethyl phosphate) or 3'-O-ethoxymethyl groups showed that the formacetal and 2'-O-Me substitutions shift the conformational equilibria of the ribose residues towards the North conformers by 5 to 12 %. Although the preference for the North conformers qualitatively correlates with increased duplex stabilities, changes in thermodynamic parameters (DeltaH degrees and TDeltaS degrees ) for formation of oligonucleotide duplexes and differences in dependence on concentrations of sodium acetate, sodium chloride and sodium perchlorate suggest that solvation effects are also important for the duplex stabilities. Overall the formacetal linkages fit well in A-type RNA duplexes, making them potentially interesting modifications for RNA-based gene-control strategies (e.g., antisense and RNA interference).
Rozners
Eriks
E
Division of Organic and Bioorganic Chemistry, MBB Scheele Laboratory, Karolinska Institutet, 17177 Stockholm, Sweden. e.rozners@neu.edu
Katkevica
Dace
D
Strömberg
Roger
R
D004952:Esters / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D008968:Molecular Conformation; D009690:Nucleic Acid Conformation; D009705:Nucleosides / Q000737:chemistry*; D009843:Oligoribonucleotides / Q000737:chemistry*; D010100:Oxygen / Q000737:chemistry; D010472:Perchlorates / Q000737:chemistry; D010766:Phosphorylation; D012313:RNA / Q000737:chemistry; D019346:Sodium Acetate / Q000737:chemistry; D012965:Sodium Chloride / Q000737:chemistry; D017670:Sodium Compounds / Q000737:chemistry; D013696:Temperature; D013816:Thermodynamics
D004952:Esters; D009705:Nucleosides; D009843:Oligoribonucleotides; D010472:Perchlorates; D017670:Sodium Compounds; D012965:Sodium Chloride; D019346:Sodium Acetate; D012313:RNA; C031068:sodium perchlorate; D010100:Oxygen