Pyrrolidino DNA with bases corresponding to the 2-oxo deletion mutants of thymine and cytosine: Synthesis and triplex-forming properties
Pyrrolidino DNA with bases corresponding to the 2-oxo deletion mutants of thymine and cytosine: Synthesis and triplex-forming properties
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DOI：
10.1002/ejoc.200700217
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发表时间：
2007-08-01
影响因子：
2.8
通讯作者：
Leumann, Christian J.
中科院分区：
文献类型：
--
作者：
Mayer, Alain;Leumann, Christian J.
吡咯烷酮DNA作为平行三联体形成的寡核苷酸的双重识别特性先前被发现强烈依赖于嘧啶碱基的性质。在这里提出的结构-活性研究中，我们能够排除这种差异结合是由于它们的2-氧功能。我们以前曾报道过吡咯烷酮c核苷与三聚体形成的2'-脱氧寡核苷酸（TFOs）的结合。在这种修饰的单元中，取代2'-脱氧糖的4'-氧原子的碱性氮原子在第三条链上引入了正电荷，这能够与带负电荷的DNA靶双链产生有利的静电相互作用。第一批具有异胞嘧啶和尿嘧啶碱基的吡罗里酮假核苷被证明可以成功识别GC碱基对，但在平行三重结合基序中无法识别AT碱基对。本文报道了两种新型的2'-脱氧吡咯里酮核苷的合成，它们的磷酰胺基块及其与tfo的结合。吡咯烷基吡啶-2- 1 （dp2P）和-2-氨基吡啶（dp2AP）分别是T和C的缺失突变体，是吡咯烷基DNA三联体结合结构-活性分析的一部分。我们通过T-m测量发现，相对于含iso-C和- u的吡咯烷酮tfo，这两种修饰都没有提高三重结合效率。这些实验清楚地表明，C4羰基功能虽然通过间接贡献对三联体结合很重要，但并不负责后两种氨基核苷的差异结合，并表明TFO构象更重要。(c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)。
The dual recognition properties of pyrrolidino DNA species as parallel triplex-forming oligonucleotides were previously found to be strongly dependent upon the nature of the pyrimidine bases. In the structure-activity study presented here we were able to exclude this differential binding being due to their 2-oxo function. We had previously reported on the incorporation of pyrrolidino C-nucleosides into triplex-forming 2'-deoxyoligonucleotides (TFOs). The basic nitrogen atom that replaces the 4'-oxygen atom of the 2'-deoxysugar in such modified units introduces a positive charge in the third strand, and this is able to produce favourable electrostatic interaction with the negatively charged DNA target duplex. A first series of pyrrolidino pseudonucleosides with the bases isocytosine and uracil proved successful for GC base-pair recognition, but was unsuccessful for AT base-pair recognition within the parallel triplex binding motif. Here we report on the synthesis of the two novel 2'-deoxypyrrolidino nucleosides carrying the bases pyridin-2-one and 2-aminopyridine, their phosphoramidite building blocks and their incorporation into TFOs. Pyrrolidinylpyridin-2-one (dp2P) and -2-aminopyridine (dp2AP), prepared as part of a structure-activity profiling of pyrrolidino DNA in triplex binding, are deletion mutants of T and C, respectively. We found by T-m measurements that neither modification increased triplex binding efficiency relative to the iso-C- and -U-containing pyrrolidino TFOs. These experiments clearly show that the C4 carbonyl function, although important for triplex binding through indirect contributions in general, is not responsible for the differential binding of the latter two aminonucleosides and suggest that TFO conformation is more important. ((c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007).