Amido-Bridged Nucleic Acids (AmNAs): Synthesis, Duplex Stability, Nuclease Resistance, and in Vitro Antisense Potency
Amido-Bridged Nucleic Acids (AmNAs): Synthesis, Duplex Stability, Nuclease Resistance, and in Vitro Antisense Potency
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DOI：
10.1002/cbic.201200506
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发表时间：
2012-11-26
期刊：
影响因子：
3.2
通讯作者：
Obika, Satoshi
中科院分区：
文献类型：
--
作者：
Yahara, Aiko;Shrestha, Ajaya Ram;Obika, Satoshi
自发现以来，2 '，4'-桥核酸（2 '，4'-BNAs）[1][或锁核酸（LNA）[2]]已被认为是反义技术的有希望的候选者，因为它们对互补链具有前所未有的高结合亲和力[1b，2]序列选择性[3]和体内应用潜力。[4，5]我们的小组[6]和其他人[7-11]正在继续努力开发基于LNA结构概念具有改进性质的其他桥接核酸。最近，我们的小组已经集中在开发新的桥接核酸与羰基功能的桥梁。由于其三角平面性，预期将羰基引入桥中以限制糖部分的柔性。到目前为止，我们已经报道了两个类似物的桥接核酸与羰基功能在其桥梁，都表现出有趣的性能。在一份报告中，我们描述了一种具有环脲结构的七元桥连核酸，[6c]它沿着高核酸酶抗性和高RNA选择性。我们最近介绍了另一类有趣的LNA类似物：异羟肟酸桥接核酸（HxNAs），[6d]它具有独特的核酸酶抗性。在开发有效的反义寡核苷酸的挑战中，寡核苷酸的体内酶消化仍然是一个重要因素。先前的研究已经表明，桥接核酸的核酸酶抗性可以通过增加桥的大小来增强，但这降低了结合亲和力。[6，7]因此需要优化桥接核酸以改善核酸酶抗性而不损失结合亲和力。为了实现这一点，研究了桥的大小和桥接核酸的性质之间的关系。在这里，我们报告了一组新的类似物的LNA与环状酰胺结构，命名为酰胺桥核酸（AmNAs）的合成和性质。这是桥接核酸中酰胺键的首次报道，尽管酰胺官能团在核酸化学中有其他用途，例如修饰磷酸键[12，13]和肽核酸（PNA）。[14]在结构上，AmNA具有类似于LNA或2 '-氨基-LNA的五元桥接结构。[15]先前关于2 '-氨基-LNA的报道表明，它们对互补链的结合亲和力与LNA相当。[15b]将羰基引入到
Since their discovery, 2’, 4’-bridged nucleic acids (2’, 4’-BNAs)[1][or locked nucleic acids (LNAs)[2]] have been considered promising candidates for antisense technology because of their unprecedented high binding affinities toward complementary strands,[1b, 2] sequence selectivities,[3] and potential for in vivo applications.[4, 5] Our group [6] and others [7–11] are continuing efforts to develop other bridged nucleic acids with improved properties based on the LNA structural concept. Recently, our group has focused on developing new bridged nucleic acids with carbonyl functionality in the bridge. The introduction of a carbonyl group into the bridge would be expected, as a consequence of its trigonal planarity, to restrict the flexibility of the sugar moiety. We have so far reported two analogues of bridged nucleic acids with carbonyl functionality in their bridges; both exhibited interesting properties. In one report we described a seven-membered bridged nucleic acid with a cyclic urea structure,[6c] which showed high nuclease resistance along with high RNA selectivity. We recently introduced another interesting class of LNA analogues: hydroxamate-bridged nucleic acids (HxNAs),[6d] which possessed unique nuclease resistance.Among the challenges to the development of a potent antisense oligonucleotide, in vivo enzymatic digestion of the oligonucleotide remains an important factor. Previous studies have shown that the nuclease resistance of a bridged nucleic acid can be enhanced by increasing the size of the bridge, but this reduces binding affinity.[6, 7] Optimization of the bridged nucleic acids to improve nuclease resistance without losing binding affinity is therefore needed. To accomplish this, the relationship between the size of the bridge and the properties of the bridged nucleic acid were investigated. Here we report the synthesis and properties of a new set of analogues of LNAs with cyclic amide structures, named amido-bridged nucleic acid (AmNAs). This is the first report of an amide linkage in a bridged nucleic acid, although amide functionality has found other uses in nucleic acid chemistry, for example, in modification of the phosphate linkage [12, 13] and in peptide nucleic acids (PNAs).[14] Structurally, an AmNA has a five-membered bridged structure similar to those of an LNA or an 2’-amino-LNA.[15] Previous reports on 2’-amino-LNAs demonstrated that their binding affinities toward complementary strands are comparable to those of LNAs.[15b] Introduction of a carbonyl group into the