Replacing the 2'-oxygen with an exocyclic methylene group reverses the stabilization effects of α-L-LNA.

The synthesis and hybridization properties of an α-L-LNA analog where the 2'-oxygen atom is replaced with an exocyclic methylene group is reported. Contrary to the β-D series where the exocyclic methylene group is extremely well tolerated, this group was very poorly tolerated in the α-L-series and lead to duplex destabilization. Modeling studies showed that the exocyclic methylene group results in a steric clash with the nucleobase 3' to the modified residue. Based on this structural model one can anticipate that replacing the 2'-oxygen atom of α-L-LNA with larger groups is likely to be detrimental to duplex stability. The model also provides insights into what type of 2',4'-bridges are most likely to be tolerated in α-L-LNA modified oligonucleotide duplexes.