Post-Synthetic Modification of Oligonucleotides via Orthogonal Amidation and Copper Catalyzed Cycloaddition Reactions,Bioconjugate Chemistry

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Post-Synthetic Modification of Oligonucleotides via Orthogonal Amidation and Copper Catalyzed Cycloaddition Reactions
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2018-06-12 00:00:00 , DOI: 10.1021/acs.bioconjchem.8b00298
Daniel Zewge ₁ , Gabor Butora ₁ , Edward C. Sherer ₁ , David M. Tellers , Daniel R. Sidler ₁ , Joseph Gouker ₁ , Greg Copeland ₁ , Vasant Jadhav , Zhen Li ₁ , Joseph Armstrong ₁ , Ian W. Davies ₁

Affiliation

An efficient multicomponent orthogonal protocol was developed for post-synthetic oligonucleotide modification using commercially available 2′-O-methyl ester and 2′-O-propargyl nucleoside scaffolds. Amidation of methyl esters with primary amines was achieved in the presence of 2′-propargyl groups which were utilized for subsequent copper catalyzed cycloaddition with GalNAc-azide. The methodology was applied to generate siRNA composed of multiple amide and triazole conjugates. Computational methods were used to illustrate the impact of substitution at the 2′-position. This a powerful post-oligomerization technique for rapidly introducing diversity to oligonucleotide design.

中文翻译：

通过正交酰胺化和铜催化的环加成反应对寡核苷酸进行合成后修饰

开发了一种有效的多组分正交方案，用于使用市售的2'- O-甲酯和2'- O-炔丙基核苷支架进行合成后的寡核苷酸修饰。在存在2'-炔丙基的情况下实现了甲基酯与伯胺的酰胺化，该芳基用于随后的铜与GalNAc-叠氮化物催化的环加成反应。该方法已应用于生成由多种酰胺和三唑共轭物组成的siRNA。使用计算方法来说明取代在2'位置的影响。这种强大的低聚后技术，可快速将多样性引入寡核苷酸设计。

更新日期：2018-06-12

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