2'-O,4'-C-ethylene-bridged nucleic acids (ENA): highly nuclease-resistant and thermodynamically stable oligonucleotides for antisense drug.
To develop antisense oligonucleotides, novel nucleosides, 2'-O,4'-C-ethylene nucleosides and their corresponding phosphoramidites, were synthesized as building blocks. The 1H NMR analysis showed that the 2'-O,4'-C-ethylene linkage of these nucleosides restricts the sugar puckering to the N-conformation as well as the linkage of 2'-O,4'-C-methylene nucleosides which are known as bridged nucleic acids (BNA) or locked nucleic acids (LNA). The ethylene-bridged nucleic acids (ENA) showed a high binding affinity for the complementary RNA strand (DeltaT(m)=+5.2 degrees C/modification) and were more nuclease-resistant than natural DNA and BNA/LNA. These results indicate that ENA have better properties as antisense oligonucleotides than BNA/LNA.
Morita
Koji
K
Exploratory Chemistry Research Laboratories, Sankyo Co., Ltd., 140-8710, Tokyo, Japan.
Hasegawa
Chikako
C
Kaneko
Masakatsu
M
Tsutsumi
Shinya
S
Sone
Junko
J
Ishikawa
Tomio
T
Imanishi
Takeshi
T
Koizumi
Makoto
M
D001952:Bridged-Ring Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D018076:DNA, Complementary / Q000737:chemistry; D015195:Drug Design; D004355:Drug Stability; D007700:Kinetics; D016376:Oligonucleotides, Antisense / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D018075:RNA, Complementary / Q000737:chemistry; D015719:Single-Strand Specific DNA and RNA Endonucleases / Q000378:metabolism; D013329:Structure-Activity Relationship; D013696:Temperature; D013936:Thymidine / Q000737:chemistry
D001952:Bridged-Ring Compounds; D018076:DNA, Complementary; D016376:Oligonucleotides, Antisense; D018075:RNA, Complementary; D015719:Single-Strand Specific DNA and RNA Endonucleases; D013936:Thymidine