title: Structural requirements for hybridization at the 5'-position are different in α-l-LNA as compared to β-D-LNA.
abstract: The synthesis and biophysical evaluation of R and S-5'-Me-α-l-LNA nucleoside phosphoramidites and modified oligo-2'-deoxyribonucleotides is reported. Synthesis of the nucleoside phosphoramidites was accomplished in multi-gram quantities starting from diacetone glucose. The 5'-methyl group in the S configuration was introduced by reacting the sugar 5'-aldehyde with MeMgBr. Synthesis of the R-5'-Me isomer was accomplished from the S-5'-Me nucleoside by a late stage inversion using Mitsunobu conditions. Evaluation of the modified oligonucleotides in thermal denaturation experiments revealed that R-5'-Me-α-l-LNA showed similar RNA affinity as α-l-LNA while the S-5'-Me analog was less stabilizing. This result is in contrast to the β-d-series where the S-5'-Me isomer showed LNA-like affinity for RNA while the R-5'-Me group completely reversed the stabilization effect on duplex thermostability.
authors.affiliation: Department of Medicinal Chemistry, Isis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA. 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: Michael E
authors.initials: ME
authors.lastname: Ostergaard
authors.forename: Eric E
authors.initials: EE
authors.lastname: Swayze
mesh_terms: D000818:Animals; D001671:Biochemistry / Q000379:methods; D001703:Biophysics / Q000379:methods; D018360:Crystallography, X-Ray / Q000379:methods; D015195:Drug Design; D005947:Glucose / Q000737:chemistry; D051379:Mice; D008956:Models, Chemical; D008968:Molecular Conformation; D009690:Nucleic Acid Conformation; D009693:Nucleic Acid Hybridization; D009705:Nucleosides / Q000737:chemistry; D009841:Oligonucleotides / Q000737:chemistry*; D009943:Organophosphorus Compounds / Q000737:chemistry; D013237:Stereoisomerism; D013696:Temperature
chemical_list: D009705:Nucleosides; D009841:Oligonucleotides; D009943:Organophosphorus Compounds; C477371:locked nucleic acid; C434331:phosphoramidite; D005947:Glucose