Synthesis and properties of GuNA purine/pyrimidine nucleosides and oligonucleotides,Organic & Biomolecular Chemistry

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Synthesis and properties of GuNA purine/pyrimidine nucleosides and oligonucleotides
Organic & Biomolecular Chemistry ( IF 2.9 ) Pub Date : 2020-11-06 , DOI: 10.1039/d0ob01970d
Shinji Kumagai ₁ , Hiroaki Sawamoto ₁ , Tomo Takegawa-Araki ₁ , Yuuki Arai ₁ , Shuhei Yamakoshi ₁ , Katsuya Yamada ₁ , Tetsuya Ohta ₁ , Eiji Kawanishi ₁ , Naohiro Horie ₂ , Takao Yamaguchi ₂ , Satoshi Obika ₃

Affiliation

We recently designed guanidine-bridged nucleic acids (GuNA), and GuNA bearing a thymine (T) nucleobase was synthesized and successfully incorporated into oligonucleotides. The GuNA-T-modified oligonucleotides possessed high duplex-forming ability towards their complementary single-stranded RNAs and were highly stable against 3′-exonuclease. Therefore, GuNA is a promissing artificial nucleic acid for therapeutic antisense oligonucleotides. We herein report the facile synthesis of GuNA phosphoramidites bearing adenine (A), guanine (G), and 5-methylcytosine (^mC) nucleobases and a robust method for the preparation of GuNA-modified oligonucleotides, even with sequences having acid-sensitive purine nucleobases. Oligonucleotides modified with GuNA-A, -G, or -^mC possessed high duplex-forming ability, similar to those modified with GuNA-T. Moreover, some of the GuNA-modified oligonucleotides were revealed to have high base discriminating ability compared with that of their natural counterparts. GuNA nucleosides exhibited no genotoxicity in bacterial reverse mutation assays. Thus, all GuNAs (GuNA-T, -A, -G, and -^mC) are now available to be examined in therapeutic applications.

中文翻译：

GuNA嘌呤/嘧啶核苷和寡核苷酸的合成与性质

我们最近设计了胍桥核酸（GuNA），合成了带有胸腺嘧啶（T）核碱基的GuNA，并成功掺入寡核苷酸中。 GuNA-T 修饰的寡核苷酸对其互补的单链 RNA 具有高双链体形成能力，并且对 3'-核酸外切酶高度稳定。因此，GuNA是一种有前途的用于治疗性反义寡核苷酸的人工核酸。我们在此报告了带有腺嘌呤 (A)、鸟嘌呤 (G) 和 5-甲基胞嘧啶 ( ^m C) 核碱基的 GuNA 亚磷酰胺的简便合成，以及一种用于制备 GuNA 修饰寡核苷酸的可靠方法，即使序列具有酸敏感嘌呤核碱基。用GuNA-A、-G或^-m C修饰的寡核苷酸具有高双链体形成能力，类似于用GuNA-T修饰的寡核苷酸。此外，一些 GuNA 修饰的寡核苷酸与天然对应物相比具有较高的碱基识别能力。 GuNA 核苷在细菌回复突变试验中没有表现出遗传毒性。因此，所有 GuNA（GuNA-T、-A、-G 和^-m C）现在均可在治疗应用中进行检查。

更新日期：2020-11-12

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