Synthesis, nucleic acid hybridization properties and molecular modelling studies of conformationally restricted 3'-O,4'-C-methylene-linked alpha-L-ribonucleotides.
Nucleotides with conformationally restricted carbohydrate rings such as locked nucleic acid (LNA), alpha-L-LNA or 2',5'-linked 3'-O,4'-C-methyleribonucleotides exhibit significant potential as building blocks for antigene and antisense strategies. 2',5'-Linked alpha-L-ribo configured monomer X (termed alpha-L-ONA) was designed as a potential structural mimic of alpha-L-LNA. The corresponding phosphoramidite building block of monomer X was obtained in five steps (10% overall yield) from the easily obtainable thymine derivative 1. Incorporation of monomer X into oligodeoxyribonucleotides (ONs) results in dramatically decreased thermal stabilities with DNA/RNA complements (DeltaTm/mod=-11.5 to -17.0 degrees C) compared to unmodified reference ONs. Less pronounced decreases (DeltaTm/mod=-4.5 to -8.5 degrees C) are observed when monomer X is incorporated into triplex forming ONs and targeted against double-stranded DNA (parallel orientation, pyrimidine motif). This biophysical data, together with modelling studies, suggest that 2',5'-linked alpha-L-ONA is a poor structural mimic of alpha-L-LNA.
Madsen
Andreas S
AS
Nucleic Acid Center, Department of Chemistry, University of Southern Denmark, DK-5230 Odense M, Denmark.
Hrdlicka
Patrick J
PJ
Kumar
T Santhosh
TS
Wengel
Jesper
J
D008958:Models, Molecular; D009690:Nucleic Acid Conformation / Q000187:drug effects; D009691:Nucleic Acid Denaturation; D009693:Nucleic Acid Hybridization / Q000379:methods*; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense / Q000737:chemistry*; D012265:Ribonucleotides / Q000138:chemical synthesis* / Q000737:chemistry*
D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D012265:Ribonucleotides; C477371:locked nucleic acid