Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, DK-5230 Odense, Denmark.
J Org Chem. 2022 Apr 15;87(8):5113-5124. doi: 10.1021/acs.joc.1c03063. Epub 2022 Apr 1.
Through the use of modified nucleotides, synthetic nucleic acids have found several fields of application within biotechnology and in the pharmaceutical industry. We have previously introduced nucleotides with an additional functional nucleobase linked to C2' of arabinonucleotides (). These double-headed nucleotides fit neatly into DNA·DNA duplexes, where they can replace the corresponding natural dinucleotides and thus condense the molecular information. Here, we introduce a 2'-deoxy version of the design with inversion of the C2' stereochemistry () with the aim of obtaining improved RNA recognition. Specifically, analogues with cytosine or isocytosine attached to C2' of 2'-deoxyuridine ( and ) were synthesized and evaluated in duplexes. Whereas the design did not outperform the design in terms of mimicking dinucleotides in nucleic acid duplexes, it was able to engage in reverse Watson-Crick pairing using its 2'-base. This was evident from the ability of the cytosine to form stable mis-matching base pairs with opposite cytosines identified as hemiprotonated C·C pairs. Furthermore, specific base-pairing with guanine was only observed for the isocytosine-bearing monomer. Very stable duplexes were obtained with monomers in each strand indicating that fully modified double-headed nucleic acid sequences could be based on the design.
通过使用修饰核苷酸，合成核酸在生物技术和制药行业的几个领域找到了应用。我们之前介绍了在阿拉伯糖核苷酸的 C2'上连接额外的功能碱基的核苷酸（）。这些双头核苷酸整齐地适合于 DNA·DNA 双链体，在双链体中，它们可以取代相应的天然二核苷酸，从而浓缩分子信息。在这里，我们引入了带有 C2'立体化学反转（）的 2'-脱氧版本的设计，目的是获得改进的 RNA 识别。具体来说，合成并评估了在双链体中连接到 2'-脱氧尿苷 C2'的胞嘧啶或异胞嘧啶的 类似物（和）。虽然在模拟核酸双链体中的二核苷酸方面，设计没有超过设计，但它能够使用其 2'-碱基进行反向 Watson-Crick 配对。这从 胞嘧啶能够与确定为半质子化的 C·C 对形成稳定的错配碱基对的能力中明显看出。此外，只有带有异胞嘧啶的 单体才观察到与鸟嘌呤的特异性碱基配对。每个链中的单体获得了非常稳定的双链体，表明完全修饰的双头核酸序列可以基于设计。
