title: 2'-O,4'-C-ethylene-bridged nucleic acids (ENA): highly nuclease-resistant and thermodynamically stable oligonucleotides for antisense drug.
abstract: 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.
authors.affiliation: Exploratory Chemistry Research Laboratories, Sankyo Co., Ltd., 140-8710, Tokyo, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Morita
authors.forename: Chikako
authors.initials: C
authors.lastname: Hasegawa
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Kaneko
authors.forename: Shinya
authors.initials: S
authors.lastname: Tsutsumi
authors.forename: Junko
authors.initials: J
authors.lastname: Sone
authors.forename: Tomio
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Imanishi
authors.forename: Makoto
authors.initials: M
authors.lastname: Koizumi
mesh_terms: 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
chemical_list: D001952:Bridged-Ring Compounds; D018076:DNA, Complementary; D016376:Oligonucleotides, Antisense; D018075:RNA, Complementary; D015719:Single-Strand Specific DNA and RNA Endonucleases; D013936:Thymidine