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

能够高效、特异性地靶向 DNA 或 RNA 的分子因其在调节特定位点的基因表达方面的潜在应用而受到极大关注。我们在基因组靶向化学方面的方法一直专注于开发具有高碱基选择性和序列选择性的反应分子。本研究分三个内容。在本研究中，研究了三种方法，包括（1）DNA/RNA杂交，（2）三链体DNA形成，（3）DNA小沟结合。在DNA/RNA杂交方法中，我们研究了可以区分单个核苷差异的新反应分子。我们已经开发出具有高选择性的新型交联剂。在这项研究中，同样的设计理念被应用于开发用于亚硝酰基转移的反应分子。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很容易脱氨基，得到尿嘧啶或胸腺嘧啶。在用于形成具有中断碱基对的稳定三链体的新核苷类似物的项目中，我们继续寻找具有WNA（W形）的新核苷类似物核苷类似物）骨架。 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。在这项研究中，多种杂环部分被引入到双环[3.3.0]辛烷骨架中，并测试了它们的三链体形成能力。因此，除了之前对 TA 中断位点具有选择性的 WNA 类似物 (WNA-βT) 之外，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 Chromomycin A3 (CRA3)，其含有被二糖和三糖取代的羟基化四氢蒽发色团。 CRA3的三糖部分被认为有助于形成Mg^2-配位二聚体，预计将通过连接到发色团部分的简单烷基来模拟作为新的模型化合物。本研究已成功证明新配体形成Mg^2-配位二聚体复合物以表现出DNA结合亲和力。较少的

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