title: Synthesis and properties of 2'-O,4'-C-ethylene-bridged nucleic acids (ENA) as effective antisense oligonucleotides.
abstract: 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 (DeltaT(m)=+3 approximately 5 degrees 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.
authors.affiliation: Exploratory Chemistry Research Laboratories, Sankyo Co., Ltd., Tokyo 140-8710, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Morita
authors.forename: Miho
authors.initials: M
authors.lastname: Takagi
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: D000475:Alkenes / Q000737:chemistry; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis*; D002942:Circular Dichroism; D003461:Crystallography; D015195:Drug Design; D004355:Drug Stability; D005030:Ethylenes / Q000737:chemistry; D015394:Molecular Structure; D023282:Nuclease Protection Assays; D009705:Nucleosides / Q000138:chemical synthesis*; D016376:Oligonucleotides, Antisense / Q000138:chemical synthesis*; D012313:RNA / Q000737:chemistry; D012260:Ribonucleases / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D044366:Transition Temperature
chemical_list: D000475:Alkenes; D001952:Bridged-Ring Compounds; D005030:Ethylenes; D009705:Nucleosides; D016376:Oligonucleotides, Antisense; D012313:RNA; C036216:ethylene; C013658:propylene; D012260:Ribonucleases