3'-C-Branched LNA-type nucleosides locked in an N-type furanose ring conformation: synthesis, incorporation into oligodeoxynucleotides, and hybridization studies.
Three protected 3'-C-branched LNA-type phosphoramidite building blocks 17, 27, and 38, containing furanose rings locked in an N-type conformation, were synthesized from a known 3-C-allyl allofuranose derivative using strategies relying on the introduction of the branching alkyl chain before condensation with the nucleobase. Synthesis of 3'-C-hydroxypropyl derivatives proved superior to synthesis of the 3'-C-hydroxyethyl derivatives, and the former was converted into the corresponding 3'-C-aminopropyl derivatives. Phosphoramidites 27 and 38 were subsequently applied on an automated DNA synthesizer leading to the introduction of three novel 3'-C-branched LNA-type monomers X, Y, and Z into oligodeoxynucleotides and studies of their effect on the hybridization properties. A duplex-stabilizing effect of introducing 3'-C-aminopropyl-LNA monomer Y, relative to 3'-C-hydroxypropyl-LNA monomer X, was observed, especially at low salt conditions. This indicates that the primary amino group of monomer Y is protonated under the hybridization conditions applied and that positioning of this positively charged group in the major groove has a significant duplex stabilizing effect. Monomer Y was by an on-column conjugation method further functionalized by a glycyl unit to give monomer Z that showed a less stabilizing effect than monomer Y.
Meldgaard
Michael
M
Department of Chemistry, University of Copenhagen, Universitetsparken 5, DK-2100 Copenhagen, Denmark.
Hansen
Flemming Gundorph
FG
Wengel
Jesper
J
D005663:Furans / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D009693:Nucleic Acid Hybridization; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry*; D009841:Oligonucleotides / Q000737:chemistry*; D016339:Spectrometry, Mass, Fast Atom Bombardment
D005663:Furans; D009705:Nucleosides; D009841:Oligonucleotides