Synthesis and properties of 2'-O,4'-C-ethylene-bridged nucleic acids (ENA) as effective antisense oligonucleotides.
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.
Morita
Koji
K
Exploratory Chemistry Research Laboratories, Sankyo Co., Ltd., Tokyo 140-8710, Japan.
Takagi
Miho
M
Hasegawa
Chikako
C
Kaneko
Masakatsu
M
Tsutsumi
Shinya
S
Sone
Junko
J
Ishikawa
Tomio
T
Imanishi
Takeshi
T
Koizumi
Makoto
M
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
D000475:Alkenes; D001952:Bridged-Ring Compounds; D005030:Ethylenes; D009705:Nucleosides; D016376:Oligonucleotides, Antisense; D012313:RNA; C036216:ethylene; C013658:propylene; D012260:Ribonucleases