Design of functional molecules for selective recognition and reaction to the duplex DNA

高效率和特异性靶向DNA或RNA的分子因其在特定位点调控基因表达的潜在应用而备受关注。我们在基因组靶向化学方面的研究重点是开发具有高碱基和序列选择性的活性分子。本研究主要包括三个内容。在本研究中，研究了三种方法，包括(1)DNA/RNA杂交，(2)三联体DNA形成，(3)DNA小槽结合。在DNA/RNA杂交的方法中，我们研究了新的反应性分子，可以区分单一核苷的差异。我们已经开发出新的高选择性交联剂。在本研究中，同样的设计理念被应用于开发一种反应性分子用于亚硝基转移。结果表明，s -亚硝基硫鸟苷可以选择性地将其亚硝基转移到胞嘧啶和5-甲基胞嘧啶的氨基上，并且亚硝基转移的氨基容易脱胺生成尿嘧啶或胸腺嘧啶。在寻找新的核苷类似物以形成具有中断碱基对的稳定三联体的项目中，我们继续寻找具有WNA （w形核苷类似物）骨架的新核苷类似物。WNA类似物在双环[3.3.0]辛烷骨架上含有一个苯环和一个杂环作为识别部分。本研究在双环[3.3.0]辛烷值骨架中引入了多种杂环组分，并对其三相形成能力进行了测试。因此，除了先前的WNA类似物（WNA-βT）对TA中断位点具有选择性外，新的类似物WNA-βC已被确定为CG中断位点的选择性碱基。在这项研究中，设计了新的dna结合配体来模拟铬霉素A3 (CRA3)，它含有一个羟基化的四氢蒽发色团，被二糖和三糖取代。CRA3的三糖部分被认为有助于形成Mg^<2+>-配位二聚体，预计将被连接在发色团部分的简单烷基模仿为新的模型化合物。本研究成功地证明了新的配体形成Mg^<2+>-配位二聚体复合物，表现出dna结合亲和力。少

Molecules that can target DNA or RNA with high efficiency and specificity are of great interest because of potential applications to modulation of gene expression at a specific site. Our approach in genome-targeting chemistry has been focused on development of reactive molecules with high base- as well as sequence selectivity. In this study, three contents. In this study, three methods have been investigated, which include (1) DNA/RNA hybridization, (2) triplex DNA formation, (3) DNA minor-groove binding.In the approach with DNA/RNA hybridization, we investigated the new reactive molecules that can discriminate a single nucleoside difference. We have already developed new cross-linking agents with high selectivity. In this study, the same design concept has been applied to develop a reactive molecule for nitrosyl group transfer. As a result, it has been revealed that S-nitroso thioguanosine can transfer its nitroso group to the amino group of cytosine and 5-methylcytosine selectively, … More and that the nitroso-transferred amino group suffers easy deamination to give uracil or thymine.In the project for new nucleoside analogs for the formation of stable triplexes having interrupting base pairs, we have continued searching new nucleoside analogs having the WNA (W-shaped nucleoside analog) skeleton. The WNA analogs contain a benzene ring and a heterocyle as a recognition part on the bicyclo[3.3.0]octane skeleton. In this study, a variety of heterocyclic parts have been introduced to the bicyclo[3.3.0]octane skeleton and their triplex-forming ability has been tested. As a result, in addition to the previous WNA analog (WNA-βT) that is selective to a TA interrupting site, the new analog WNA-βC has been identified as a selective base for a CG interrupting site.In this study, new DNA-binding ligands were designed to mimic Chromomycin A3 (CRA3) which contains a hydroxylated tetrahydroanthracene chromophore substituted with di- and tri-saccharides. The trisaccharide part of CRA3 that is supposed to contribute to form the Mg^<2+>-coordinated dimer was expected to be mimicked by a simple alkyl group attached to the chromophore part as new model compounds. The present study has successfully demonstrated that the new ligands form Mg^<2+>-coordinated dimer complexes to exhibit DNA-binding affinity. Less