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

Abstract 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.