Synthesis and properties of adenosine oligonucleotide analogues containing methylene groups in place of phosphodiester 5'-oxygens.
Synthesis and properties of adenosine oligonucleotide analogues containing methylene groups in place of phosphodiester 5'-oxygens.
复制标题
含有亚甲基取代磷酸二酯 5-氧的腺苷寡核苷酸类似物的合成和性质。
DOI：
10.1021/bi00086a017
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发表时间：
1993
期刊：
影响因子：
2.9
通讯作者：
Gilham,PT
中科院分区：
文献类型：
--
作者：
Breaker,RR;Gough,GR;Gilham,PT
1993年6月3日接收的修订版Mandalpt ®摘要：ADP类似物，其中5 '-氧已被亚甲基取代，可以通过将S'-脱氧-S '-膦酰基甲基腺苷与无机磷酸盐缩合来制备。在酶多核苷酸磷酸化酶和Mg 2+或Mn 2+存在下，该类似物容易聚合到引物AA上。初始产物为AA（-cA）n-cA形式（其中和“-c”分别代表正常磷酸二酯键和其中5 '-氧被亚甲基取代的键）。用碱处理这些化合物得到腺苷2 '（3'）-磷酸和仅含膦亚甲基键的系列（A（-cA）n-cA。十聚体A（-cA）g-cA与两个U（-U）8-U分子相互作用形成三重标准结构，其稳定性与由A（-A）gA和U（-U）sU形成的类似复合物所表现出的稳定性相似。这种性质，沿着这些寡聚体类似物对切割磷和S ′-氧之间的磷酸二酯键的核酸酶的抗性，应该为膦酰基亚甲基键在使用反义策略的治疗药物设计方案中的应用提供了强有力的理论基础。通过利用寡聚体的核苷酸序列与其沃森形成稳定复合物的能力，设计合成的寡核苷酸结构以用作基因表达或其它核酸功能的抑制剂。细胞内的补体。已经合成了大量的寡核苷酸类似物结构，并为此目的进行了研究[Uhlmann和Peyman（1990）综述]。结构修饰通常涉及核苷酸间连接的改变，这允许寡聚体保留其形成对应于天然形状的碱基配对双链体的能力，同时赋予对通常在体内破坏分子的核酸酶的一定抗性。本研究[初步报告，见断路器等。（1990）]涉及含有亚甲基取代其5 ′-氧的腺苷寡聚体的制备，这种取代对它们与尿苷寡聚体相互作用的影响，以及它们对核酸酶切割的敏感性。
Revised Manuscript Received June 3, 1993® abstract: The ADP analogue in which the 5'-oxygen has been replaced by a methylene group can be prepared by condensing S'-deoxy-S'-phosphonomethyladenosine with inorganic phosphate. This analogue readily polymerizes onto the primer AA in the presence of the enzyme polynucleotide phosphorylase and either Mg2+ or Mn2+. The initial products are of the form AA (-cA)„-cA (where and “-c” stand for the normal phosphodiester linkage and the linkage in which the 5'-oxygen is replaced with the methylene group, respectively). Treatment of these with alkali yields adenosine 2'(3')-phosphate and the series (A (-cA)„-cA containing only phosphonomethylene linkages. The decamer A (-cA) g-cA interacts with two molecules of U (-U) 8-U to form a triple-standard structure that has a stability similar to that exhibited by the analogous complex formed from A (-A) gA and U (-U) sU. This property, along with the resistance of these oligomer analogues toward nucleases that cleave phosphodiester linkages between the phosphorus and the S'-oxygen, should provide a strong rationale for application of phosphonomethylene linkages in schemes for therapeutic drug design that use the antisense strategy.In the “antisense” strategy of drug development, synthetic oligonucleotide structures are designed to serve as inhibitors of gene expression or other nucleic acid functions by exploiting the capacity of the oligomer’s nucleotide sequence to form a stable complex with its Watson-Crick complement within the cell. A large number of oligonucleotide analogue structures have been synthesized and studied for this purpose [reviewed by Uhlmann and Peyman (1990)]. The structural modifi-cations have usually involved changes in the internucleotide linkage which permit the oligomer to conserve its capacity to form base-paired duplexes corresponding to the natural shape while at the same time conferring some resistance to nucleases that would normally destroy the molecule in vivo. The present study [for a preliminary report, see Breaker et al.(1990)] concerns the preparation of adenosine oligomerscontaining methylene groups in place of their 5'-oxygens, the effects of such substitution on their interaction with uridine oligomers, and their susceptibility to nuclease cleavage.