Synthesis and properties of 2′-O, 4′-C-ethylene-bridged nucleic acids (ENA) as effective antisense oligonucleotides

K Morita, M Takagi, C Hasegawa, M Kaneko… - Bioorganic & medicinal …, 2003 - Elsevier
K Morita, M Takagi, C Hasegawa, M Kaneko, S Tsutsumi, J Sone, T Ishikawa, T Imanishi…
Bioorganic & medicinal chemistry, 2003Elsevier
Novel bicyclo nucleosides, 2′-O, 4′-C-ethylene nucleosides and 2′-O, 4′-C-propylene
nucleosides, were synthesized as building blocks for antisense oligonucleotides to further
optimize the 2′-O, 4′-C-methylene-linkage of bridged nucleic acids (2′, 4′-BNA) or
locked nucleic acids (LNA). Both the 2′-O, 4′-C-ethylene-and propylene-linkage within
these nucleosides restrict the sugar puckering to the N-conformation of RNA as do 2′, 4′-
BNA/LNA. Furthermore, ethylene-bridged nucleic acids (ENA) having 2′-O, 4′-C-ethylene …
Novel bicyclo nucleosides, 2′-O,4′-C-ethylene nucleosides and 2′-O,4′-C-propylene nucleosides, were synthesized as building blocks for antisense oligonucleotides to further optimize the 2′-O,4′-C-methylene-linkage of bridged nucleic acids (2′,4′-BNA) or locked nucleic acids (LNA). Both the 2′-O,4′-C-ethylene- and propylene-linkage within these nucleosides restrict the sugar puckering to the N-conformation of RNA as do 2′,4′-BNA/LNA. Furthermore, ethylene-bridged nucleic acids (ENA) having 2′-O,4′-C-ethylene nucleosides had considerably increased the affinity to complementary RNA, and were as high as that of 2′,4′-BNA/LNA (ΔTm=+3∼5°C per modification). On the other hand, addition of 2′-O,4′-C-propylene modifications in oligonucleotides led to a decrease in the affinity to complementary RNA. As for the stability against nucleases, incorporation of one 2′-O,4′-C-ethylene or one 2′-O,4′-C-propylene nucleoside into oligonucleotides considerably increased their resistance against exonucleases to an extent greater than 2′,4′-BNA/LNA. These results indicate that ENA is more suitable as an antisense oligonucleotide and is expected to have better antisense activity than 2′,4′-BNA/LNA.
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