Based on the above and on the remarkable properties of the 2′-O,4′-C-
methylene bridged LNA monomers it was decided to synthesise oligonucleotides comprising one or more 2′-O,4′-C-
methylene-β-D-xylofuranosyl
nucleotide monomer(s) as the first stereoisomer of LNA modified oligonucleotides. Modelling clearly indicated the xylo-LNA monomers to be locked in an N-type
furanose conformation. Whereas the parent 2′-deoxy-β-D-xylofuranosyl nucleosides were shown to adopt mainly an N-type
furanose conformation, the
furanose ring of the 2′-deoxy-β-D-xylofuranosyl monomers present in xylo-
DNA were shown by conformational analysis and
computer modelling to prefer an S-type conformation thereby minimising steric repulsion between the
nucleobase and the 3′-O-phopshate group (Seela, F.; Wömer, Rosemeyer, H. Helv. Chem. Acta 1994, 77, 883). As no report on the hybridisation properties and binding mode of xylo-configurated oligonucleotides in an
RNA context was believed to exist, it was the aim to synthesise 2′-O,4′-C-
methylene-β-D-xylofuranosyl
nucleotide monomer and to study the
thermal stability of oligonucleotides comprising this
monomer. The results showed that fully modified or almost fully modified Xylo-LNA is useful for high-affinity targeting of complementary nucleic acids. When taking into consideration the inverted
stereochemistry at C-3′ this is a surprising fact. It is likely that Xylo-LNA monomers, in a sequence context of Xylo-
DNA monomers, should have an affinity-increasing effect.