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Automated Solid-Phase Click Synthesis of Oligonucleotide Conjugates: From Small Molecules to Diverse N-Acetylgalactosamine Clusters
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2017-10-04 00:00:00 , DOI: 10.1021/acs.bioconjchem.7b00462
Valentina M. Farzan 1 , Egor A. Ulashchik 2 , Yury V. Martynenko-Makaev 2 , Maksim V. Kvach 2 , Ilya O. Aparin 3 , Vladimir A. Brylev 3 , Tatiana A. Prikazchikova 1 , Svetlana Yu. Maklakova 4 , Alexander G. Majouga 4, 5 , Alexey V. Ustinov 3 , German A. Shipulin 6 , Vadim V. Shmanai 2 , Vladimir A. Korshun 3, 7 , Timofei S. Zatsepin 1, 4, 6
Affiliation  

We developed a novel technique for the efficient conjugation of oligonucleotides with various alkyl azides such as fluorescent dyes, biotin, cholesterol, N-acetylgalactosamine (GalNAc), etc. using copper-catalysed alkyne–azide cycloaddition on the solid phase and CuI·P(OEt)3 as a catalyst. Conjugation is carried out in an oligonucleotide synthesizer in fully automated mode and is coupled to oligonucleotide synthesis and on-column deprotection. We also suggest a set of reagents for the construction of diverse conjugates. The sequential double-click procedure using a pentaerythritol-derived tetraazide followed by the addition of a GalNAc or Tris–GalNAc alkyne gives oligonucleotide–GalNAc dendrimer conjugates in good yields with minimal excess of sophisticated alkyne reagents. The approach is suitable for high-throughput synthesis of oligonucleotide conjugates ranging from fluorescent DNA probes to various multi-GalNAc derivatives of 2′-modified siRNA.

中文翻译:

寡核苷酸缀合物的自动固相点击合成:从小分子到不同的N-乙酰半乳糖胺簇

我们开发了一种新技术,可通过在固相上使用铜催化的炔-叠氮化物环加成反应,将寡核苷酸与各种烷基叠氮化物(例如荧光染料,生物素,胆固醇,N-乙酰半乳糖胺(GalNAc)等)进行有效偶联,该方法是在铜上催化铜-炔-叠氮化物环加成的。 OEt)3作为催化剂。在寡核苷酸合成仪中以全自动模式进行缀合,并偶联至寡核苷酸合成和柱上脱保护。我们还建议了一套用于构建多种缀合物的试剂。使用季戊四醇衍生的四叠氮化物的顺序双击程序,然后添加GalNAc或Tris-GalNAc炔烃,可以以极高的收率获得寡核苷酸-GalNAc树枝状大分子共轭物,而所需的复杂炔烃试剂却极少。该方法适用于寡核苷酸偶联物的高通量合成,寡核苷酸偶联物的范围从荧光DNA探针到2'-修饰的siRNA的各种multi-GalNAc衍生物。
更新日期:2017-10-04
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