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

2002; American Chemical Society; Volume: 124; Issue: 10 Linguagem: Inglês

10.1021/ja0168763

1943-2984

Mads D. Sørensen, Lisbet Kværnø, Torsten Bryld, Anders E. Håkansson, Birgit Verbeure, Gilles Gaubert, Piet Herdewijn, Jesper Wengel,

RNA and protein synthesis mechanisms

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.