α-l-ribo-Configured Locked Nucleic Acid (α-L-LNA): Synthesis and Properties

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Abstract
The syntheses of monomeric nucleosides and 3‘-O-phosphoramidite building blocks en route to α-l -ribo-configured locked nucleic acids (α-L-LNA), composed entirely of α-L-LNA monomers (α-l-ribo configuration) or of a mixture of α-L-LNA and DNA monomers (β-d-ribo configuration), are described and the α-L-LNA oligomers are studied. Bicyclic 5-methylcytosin-1-yl and adenin-9-yl nucleoside derivatives have been prepared and the phosphoramidite approach has been used for the automated oligomerization leading to α-L-LNA oligomers. Binding studies revealed very efficient recognition of single-stranded DNA and RNA target oligonucleotide strands. Thus, stereoirregular α-L-LNA 11-mers containing a mixture of α-L-LNA monomers and DNA monomers (“mix-mer α-L-LNA”) were shown to display ΔTm values of +1 to +3 °C per modification toward DNA and +4 to +5 °C toward RNA when compared with the corresponding unmodified DNA·DNA and DNA·RNA reference duplexes. The corresponding ΔTm values per modification for the stereoregular fully modified α-L-LNA were determined to be +4 °C (against DNA) and +5 °C (against RNA). 11-Mer α-L-LNAs (mix-mer α- L-LNA or fully modified α- l-LNA) were shown in vitro to be significantly stabilized toward 3‘-exonucleolytic degradation. A duplex formed between RNA and either mix-mer α-L-LNA or fully modified α-L-LNA induced in vitro Escherichia coli RNase H-mediated cleavage, albeit very slow, of the RNA targets at high enzyme concentrations.