Design, synthesis, and properties of 2′,4′-BNANC:: A bridged nucleic acid analogue
Design, synthesis, and properties of 2′,4′-BNANC:: A bridged nucleic acid analogue
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DOI：
10.1021/ja710342q
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发表时间：
2008-04-09
影响因子：
15
通讯作者：
Imanishi, Takeshi
中科院分区：
文献类型：
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作者：
Rahman, S. M. Abdur;Seki, Sayori;Imanishi, Takeshi
设计并高效合成了新型桥联核酸类似物2 '，4'-BNA（NC）（2 '-O，4'-C-aminomethylene bridged nucleic acid），其含有N-O键的六元桥联结构，证明了分子内NC键形成关键反应一锅法构建全氢-1，2-恶嗪环（11和12）。合成了3种2 '，4'-BNA（NC）单体（2 '，4'-BNA（NC）[NH]、[NMe]和[NBn]）并将其掺入寡核苷酸中，研究了它们的性质，并与2 '，4'-BNA（LNA）修饰的寡核苷酸进行了比较。与2 '，4'-BNA（LNA）-改性β-内酰胺相比，发现2 '，4'-BNANC同系物具有：（i）对RNA互补物的相等或更高的结合亲和力，具有优异的单错配辨别能力，（ii）好得多的RNA选择性结合，（iii）更强和更多的序列选择性三链体形成特征，和（iv）极高的核酸酶抗性，甚至高于S-p-硫代磷酸酯类似物。2 '，4'-BNA（NC）修饰的寡核苷酸具有这些优异的特性，在反义和反基因技术中显示出巨大的应用前景。
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 oligonucleoticles. Compared to 2',4'-BNA (LNA)-modified oligonucleoticles, 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 S-p-phosphorthioate analogue. 2',4'-BNA(NC)-modified oligonucleotides with these excellent profiles show great promise for applications in antisense and antigene technologies.