title: 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.
authors.affiliation: Department of Medicinal Chemistry, Isis Pharmaceuticals, Inc, 1891 Rutherford Road, Carlsbad, CA 92008, United States. pseth@isisph.com
authors.forename: Punit P
authors.initials: PP
authors.lastname: Seth
authors.forename: Charles R
authors.initials: CR
authors.lastname: Allerson
authors.forename: Andres
authors.initials: A
authors.lastname: Berdeja
authors.forename: Eric E
authors.initials: EE
authors.lastname: Swayze
mesh_terms: D009690:Nucleic Acid Conformation; D009841:Oligonucleotides / Q000737:chemistry*; D010100:Oxygen / Q000737:chemistry*; D044366:Transition Temperature
chemical_list: D009841:Oligonucleotides; C477371:locked nucleic acid; D010100:Oxygen