title: alpha-L-ribo-configured locked nucleic acid (alpha-L-LNA): synthesis and properties.
abstract: The syntheses of monomeric nucleosides and 3'-O-phosphoramidite building blocks en route to alpha-L-ribo-configured locked nucleic acids (alpha-L-LNA), composed entirely of alpha-L-LNA monomers (alpha-L-ribo configuration) or of a mixture of alpha-L-LNA and DNA monomers (beta-D-ribo configuration), are described and the alpha-L-LNA oligomers are studied. Bicyclic 5-methylcytosin-1-yl and adenine-9-yl nucleoside derivatives have been prepared and the phosphoramidite approach has been used for the automated oligomerization leading to alpha-L-LNA oligomers. Binding studies revealed very efficient recognition of single-stranded DNA and RNA target oligonucleotide strands. Thus, stereoirregular alpha-L-LNA 11-mers containing a mixture of alpha-L-LNA monomers and DNA monomers ("mix-mer alpha-L-LNA") were shown to display DeltaT(m) values of +1 to +3 degrees C per modification toward DNA and +4 to +5 degrees C toward RNA when compared with the corresponding unmodified DNA x DNA and DNA x RNA reference duplexes. The corresponding DeltaT(m) values per modification for the stereoregular fully modified alpha-L-LNA were determined to be +4 degrees C (against DNA) and +5 degrees C (against RNA). 11-Mer alpha-L-LNAs (mix-mer alpha- L-LNA or fully modified alpha- L-LNA) were shown in vitro to be significantly stabilized toward 3'-exonucleolytic degradation. A duplex formed between RNA and either mix-mer alpha-L-LNA or fully modified alpha-L-LNA induced in vitro Escherichia coli RNase H-mediated cleavage, albeit very slow, of the RNA targets at high enzyme concentrations.
authors.affiliation: Department of Chemistry, University of Copenhagen, Universitetsparken 5, DK-2100 Copenhagen, Denmark.
authors.forename: Mads D
authors.initials: MD
authors.lastname: Sørensen
authors.forename: Lisbet
authors.initials: L
authors.lastname: Kvaernø
authors.forename: Torsten
authors.initials: T
authors.lastname: Bryld
authors.forename: Anders E
authors.initials: AE
authors.lastname: Håkansson
authors.forename: Birgit
authors.initials: B
authors.lastname: Verbeure
authors.forename: Gilles
authors.initials: G
authors.lastname: Gaubert
authors.forename: Piet
authors.initials: P
authors.lastname: Herdewijn
authors.forename: Jesper
authors.initials: J
authors.lastname: Wengel
mesh_terms: D002942:Circular Dichroism; D004926:Escherichia coli / Q000201:enzymology; D006358:Hot Temperature; D008968:Molecular Conformation; D009696:Nucleic Acids / Q000138:chemical synthesis / Q000737:chemistry*; D009943:Organophosphorus Compounds / Q000138:chemical synthesis / Q000737:chemistry; D043264:Phosphodiesterase I; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry; D011684:Purine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry; D016914:Ribonuclease H / Q000737:chemistry
chemical_list: D009696:Nucleic Acids; D009943:Organophosphorus Compounds; D011684:Purine Nucleosides; D011741:Pyrimidine Nucleosides; C434331:phosphoramidite; D016914:Ribonuclease H; D010727:Phosphoric Diester Hydrolases; D043264:Phosphodiesterase I