Synthesis and application of highly reactive amino linkers for functional oligonucleotides.
Synthesis and application of highly reactive amino linkers for functional oligonucleotides.
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DOI：
10.1002/0471142700.nc0448s48
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发表时间：
2012-03-01
影响因子：
--
通讯作者：
Komatsu, Yasuo
中科院分区：
文献类型：
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作者：
Kojima, Naoshi;Komatsu, Yasuo
寡核苷酸通过与各种分子的结合而功能化，脂肪族氨基连接物经常被用来作为其修饰的系绳。本单元描述了具有氨基甲酸酯结构的新型氨基连接物的合成和应用。伯胺的两个主要化学性质是由氨基甲酸酯基团的邻位效应引起的，在氨基甲酸乙酯结构中发现这两个基团是最佳的。首先，在非常温和的酸性条件下，氨基甲酸乙酯中的疏水单甲氧基三苯基可以被快速去除，而在标准脂肪胺中，即使在高酸浓度下也不能完成脱保护。这一显著特征使得通过利用单甲氧基三丁基与反相树脂的疏水相互作用能够方便地纯化氨基修饰的寡核苷酸。其次，氨基甲酸酯键的引入降低了邻伯胺的pK(A)值，导致与各种功能分子的共轭产率增加，如那些具有活性酯的分子。具有氨基甲酸乙酯键的新型氨基连接物具有很强的活性，可用于制备各种功能性寡核苷酸。
Oligonucleotides are functionalized by conjugation with a variety of molecules, and aliphatic amino linkers have been frequently used as a tether for their modifications. This unit describes the syntheses and applications of novel amino linkers having a carbamate structure. Two major chemical properties of the primary amine are induced by the neighboring effect of the carbamate group, which are found to be optimum in an aminoethyl carbamate structure. First, the hydrophobic monomethoxytrityl group can be rapidly removed from the aminoethyl carbamate under very mild acidic conditions, while the deprotection is not completed in standard aliphatic amines even under high acid concentration. This significant feature enables the convenient purification of amino-modified oligonucleotides by using the hydrophobic interaction of the monomethoxytrityl group with a reverse-phase resin. Second, the introduction of the carbamate linkage reduces the pK(a) value of the neighboring primary amine, resulting in an increase in the conjugation yields with various functional molecules, such as those having active esters. The novel amino linkers that have an aminoethyl carbamate linkage indicate potent activity and are applicable for the preparation of various functional oligonucleotides.