title: Synthesis and biophysical evaluation of 3'-Me-α-L-LNA - Substitution in the minor groove of α-L-LNA duplexes.
abstract: The synthesis and biophysical evaluation of 3'-Me-α-L-LNA is reported. The synthesis of the nucleoside building block phosphoramidite was accomplished starting from diacetone glucose. The 3'-Me group was introduced in the desired configuration by hydride mediated opening of an exocyclic epoxide. Inversion of the 2'-hydroxyl group was achieved by means of an oxidation/reduction sequence followed by cyclization onto a 5'-leaving group to assemble the [2.2.1] ring system. Biophysical evaluation of 3'-Me-α-L-LNA modified oligonucleotides showed good duplex thermal stabilizing properties which were similar to α-L-LNA. Mismatch discrimination experiments revealed that 3'-Me-α-L-LNA possess slightly enhanced discrimination properties for the GU wobble base-pair as compared to related nucleic acid analogs.
authors.affiliation: Department of Medicinal Chemistry, Isis Pharmaceuticals, 1891 Rutherford Road, Carlsbad, CA 92008, United States. pseth@isisph.com
authors.forename: Punit P
authors.initials: PP
authors.lastname: Seth
authors.forename: Charles A
authors.initials: CA
authors.lastname: Allerson
authors.forename: Michael E
authors.initials: ME
authors.lastname: Østergaard
authors.forename: Eric E
authors.initials: EE
authors.lastname: Swayze
mesh_terms: D008958:Models, Molecular; D008968:Molecular Conformation; D009841:Oligonucleotides / Q000138:chemical synthesis / Q000737:chemistry*; D013237:Stereoisomerism; D013696:Temperature
chemical_list: D009841:Oligonucleotides; C477371:locked nucleic acid