Design, synthesis, and properties of 2',4'-BNA(NC): a bridged nucleic acid analogue.
The novel bridged nucleic-acid analogue 2',4'-BNA(NC) (2'-O,4'-C-aminomethylene bridged nucleic acid), containing a six-membered bridged structure with an N-O linkage, was designed and synthesized efficiently, demonstrating a one-pot intramolecular NC bond-forming key reaction to construct a perhydro-1,2-oxazine ring (11 and 12). Three monomers of 2',4'-BNA(NC) (2',4'-BNA(NC)[NH], [NMe], and [NBn]) were synthesized and incorporated into oligonucleotides, and their properties were investigated and compared with those of 2',4'-BNA (LNA)-modified oligonucleotides. Compared to 2',4'-BNA (LNA)-modified oligonucleotides, 2',4'-BNA(NC) congeners were found to possess: (i) equal or higher binding affinity against an RNA complement with excellent single-mismatch discriminating power, (ii) much better RNA selective binding, (iii) stronger and more sequence selective triplex-forming characters, and (iv) immensely higher nuclease resistance, even higher than the S(p)-phosphorthioate analogue. 2',4'-BNA(NC)-modified oligonucleotides with these excellent profiles show great promise for applications in antisense and antigene technologies.
Rahman
S M Abdur
SM
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
Seki
Sayori
S
Obika
Satoshi
S
Yoshikawa
Haruhisa
H
Miyashita
Kazuyuki
K
Imanishi
Takeshi
T
D001483:Base Sequence; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D003851:Deoxyribonucleases / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D009711:Nucleotides / Q000138:chemical synthesis* / Q000737:chemistry; D009841:Oligonucleotides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D013056:Spectrophotometry, Ultraviolet
C527205:2',4'-BNA(NC); D001952:Bridged-Ring Compounds; D009711:Nucleotides; D009841:Oligonucleotides; D003851:Deoxyribonucleases; D010727:Phosphoric Diester Hydrolases