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

能够以高效率和特异性靶向DNA或RNA的分子由于在特定位点调节基因表达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和序列选择性的反应性分子。在本研究中，有三个内容。本研究主要研究了（1）DNA/RNA杂交、（2）三链体DNA形成、（3）DNA小沟结合三种方法，其中DNA/RNA杂交方法研究了能够区分单个核苷差异的新型反应分子。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，同样的设计概念已被应用到开发一个反应性分子的亚硝酰基转移。结果表明，S-亚硝基硫代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， 关于我们 亚硝基转移的氨基容易脱氨基而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形核苷类似物）骨架的新核苷类似物。WNA类似物含有苯环和杂环作为双环[3.3.0]辛烷骨架上的识别部分。在本研究中，各种杂环部分已被引入到双环[3.3.0]辛烷骨架和他们的三链体形成能力进行了测试。本研究设计了一种新的模拟色霉素A3（CRA 3）的DNA结合配体，该配体含有一个羟基化的四氢蒽发色团，并被二、三取代基取代。CRA 3的三糖部分被认为有助于形成Mg^<2+>-配位的二聚体，预计将被连接到发色团部分的简单烷基模拟为新的模型化合物。目前的研究已经成功地证明了新的配体形成Mg^<2+>配位的二聚体复合物，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