O6-(benzotriazol-1-yl)inosine derivatives:: Easily synthesized, reactive nucleosides
O6-(benzotriazol-1-yl)inosine derivatives:: Easily synthesized, reactive nucleosides
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DOI：
10.1021/ja064682n
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发表时间：
2007-01-31
影响因子：
15
通讯作者：
Lakshman, Mahesh K.
中科院分区：
文献类型：
--
作者：
Bae, Suyeal;Lakshman, Mahesh K.
一类新的O-6-（苯并三唑-1-基）肌苷及其相应的2 ′-脱氧衍生物可以通过糖保护或未保护的肌苷或2 ′-脱氧肌苷核苷与1H-苯并三唑-1-基氧基-三（二甲氨基）磷鎓六氟磷酸盐（BOP）之间的反应方便地制备。该反应似乎通过核苷鏻盐进行，并且在没有任何另外的亲核试剂的情况下，释放的1-羟基苯并三唑与形成的鏻盐反应，产生必需的O-6-（苯并三唑-1-基）肌苷或2 ′-脱氧肌苷衍生物。鏻盐的分离和表征以及通过P-31{H-1} NMR的分析似乎与该反应途径一致。所得的O-6-（苯并三唑-1-基）肌苷衍生物作为亲电子核苷是有效的，与各种亲核试剂如醇、酚、胺和硫醇进行容易的反应。也已经从O-6-（苯并三唑-1-基）-2 '-脱氧肌苷衍生物合成了不寻常的和具有挑战性的核苷衍生物，例如芳基桥接的二聚体、核苷-氨基酸缀合物和核苷-核苷二聚体。最后，制备了一种完全保护的DNA结构单元，O-6-（苯并三唑-1-基）-2 '-脱氧肌苷5'-O-DMT 3 '-O-亚磷酰胺，并对其用于DNA修饰进行了初步评价。这些研究的结果表明了几个重要的事实：一个单一的，简单的方法提供了一类稳定的，可分离的核糖和2 '-脱氧核糖核苷衍生物，具有良好的反应性SNAr化学与广泛的亲核试剂。此外，苯并三唑基核苷亚磷酰胺似乎是一种合适的试剂，用于掺入DNA中进行位点特异性DNA修饰。
A novel class of O-6-(benzotriazol-1-yl)inosine as well as the corresponding 2'-deoxy derivatives can be conveniently prepared by a reaction between sugar-protected or -unprotected inosine or 2'-deoxyinosine nucleosides and 1H-benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP). The reaction appears to proceed via a nucleoside phosphonium salt, and in the absence of any additional nucleophile, the released 1-hydroxybenzotriazole undergoes reaction with the formed phosphonium salt leading to the requisite O-6-(benzotriazol-1-yl)inosine or 2'-deoxyinosine derivatives. Isolation and characterization of the phosphonium salt as well as analysis by P-31{H-1} NMR appear to be consistent with this reaction pathway. The resulting O-6-(benzotriazol-1-yl)inosine derivatives are effective as electrophilic nucleosides, undergoing facile reactions with a variety of nucleophiles such as alcohols, phenols, amines, and a thiol. Unusual and challenging nucleoside derivatives such as an aryl-bridged dimer, a nucleoside-amino acid conjugate, and a nucleoside-nucleoside dimer have also been synthesized from the O-6-(benzotriazol-1-yl)-2'-deoxyinosine derivative. Finally, a fully protected DNA building block, the O-6-(benzotriazol-1-yl)-2'-deoxyinosine 5'-O-DMT 3'-O-phosphoramidite, has been prepared and a preliminary evaluation of its use for DNA modification has been performed. Results from these studies indicate several important facts: A single, simple methodological approach provides a class of stable, isolable ribo and 2'-deoxyribonucleoside derivatives that possess excellent reactivity for SNAr chemistry with a wide range of nucleophiles. Also, a benzotriazolyl nucleoside phosphoramidite appears to be a suitable reagent for incorporation into DNA for purposes of site-specific DNA modification.