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Design, Synthesis, and Properties of 2‘,4‘-BNANC:  A Bridged Nucleic Acid Analogue

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posted on 09.04.2008, 00:00 by S. M. Abdur Rahman, Sayori Seki, Satoshi Obika, Haruhisa Yoshikawa, Kazuyuki Miyashita, Takeshi Imanishi
The novel bridged nucleic-acid analogue 2‘,4‘-BNANC (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‘-BNANC (2‘,4‘-BNANC[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‘-BNANC 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 Sp-phosphorthioate analogue. 2‘,4‘-BNANC-modified oligonucleotides with these excellent profiles show great promise for applications in antisense and antigene technologies.