减少 3-(2-氰乙基)胸苷杂质的简化寡核苷酸去磷工艺。

IF 4 2区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Nucleic acid therapeutics Pub Date : 2024-04-01 Epub Date: 2024-02-05 DOI:10.1089/nat.2023.0060

Xuan Zhou, Xianglin Shi, Yannick Fillon, Firoz Antia, Thomas Pickel, Jing Yang, William Zhang, Armin Delavari, Jiabao Zhang

{"title":"减少 3-(2-氰乙基)胸苷杂质的简化寡核苷酸去磷工艺。","authors":"Xuan Zhou, Xianglin Shi, Yannick Fillon, Firoz Antia, Thomas Pickel, Jing Yang, William Zhang, Armin Delavari, Jiabao Zhang","doi":"10.1089/nat.2023.0060","DOIUrl":null,"url":null,"abstract":"Oligonucleotides have emerged as valuable new therapeutics. Presently, oligonucleotide manufacturing consists in a series of stepwise additions until the full-length product is obtained. Deprotection of the phosphorus backbone before cleavage and deprotection (C&D) by ammonolysis is necessary to control the 3-(2-cyanoethyl) thymidine (CNET) impurity. In this study, we demonstrate that the use of piperazine as a scavenger of acrylonitrile allows phosphorus deprotection and C&D to be combined in a single step. This reduces solvent consumption, processing time, and CNET levels. Additionally, we showed that substitution of piperazine for triethylamine in the phosphorus deprotection step of supported-synthesis leads to reduced reaction times and lower levels of CNET impurities.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"83-89"},"PeriodicalIF":4.0000,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Simplified Oligonucleotide Phosphorus Deprotection Process with Reduced 3-(2-Cyanoethyl) Thymidine Impurities.\",\"authors\":\"Xuan Zhou, Xianglin Shi, Yannick Fillon, Firoz Antia, Thomas Pickel, Jing Yang, William Zhang, Armin Delavari, Jiabao Zhang\",\"doi\":\"10.1089/nat.2023.0060\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Oligonucleotides have emerged as valuable new therapeutics. Presently, oligonucleotide manufacturing consists in a series of stepwise additions until the full-length product is obtained. Deprotection of the phosphorus backbone before cleavage and deprotection (C&D) by ammonolysis is necessary to control the 3-(2-cyanoethyl) thymidine (CNET) impurity. In this study, we demonstrate that the use of piperazine as a scavenger of acrylonitrile allows phosphorus deprotection and C&D to be combined in a single step. This reduces solvent consumption, processing time, and CNET levels. Additionally, we showed that substitution of piperazine for triethylamine in the phosphorus deprotection step of supported-synthesis leads to reduced reaction times and lower levels of CNET impurities.\",\"PeriodicalId\":19412,\"journal\":{\"name\":\"Nucleic acid therapeutics\",\"volume\":\" \",\"pages\":\"83-89\"},\"PeriodicalIF\":4.0000,\"publicationDate\":\"2024-04-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nucleic acid therapeutics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1089/nat.2023.0060\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/2/5 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nucleic acid therapeutics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1089/nat.2023.0060","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/2/5 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

摘要

寡核苷酸已成为有价值的新疗法。目前，寡核苷酸的生产包括一系列逐步添加的过程，直至获得全长产品。为了控制 3-（2-氰乙基）胸苷（CNET）杂质，有必要在通过氨解进行裂解和脱保护（C&D）之前对磷骨架进行脱保护。在这项研究中，我们证明了使用哌嗪作为丙烯腈的清除剂，可以在一个步骤中将磷脱保护和 C&D 结合在一起。这减少了溶剂消耗、加工时间和 CNET 水平。此外，我们还表明，在支撑合成的磷脱保护步骤中用哌嗪替代三乙胺可缩短反应时间，降低 CNET 杂质含量。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

查看原文本刊更多论文

Simplified Oligonucleotide Phosphorus Deprotection Process with Reduced 3-(2-Cyanoethyl) Thymidine Impurities.

Oligonucleotides have emerged as valuable new therapeutics. Presently, oligonucleotide manufacturing consists in a series of stepwise additions until the full-length product is obtained. Deprotection of the phosphorus backbone before cleavage and deprotection (C&D) by ammonolysis is necessary to control the 3-(2-cyanoethyl) thymidine (CNET) impurity. In this study, we demonstrate that the use of piperazine as a scavenger of acrylonitrile allows phosphorus deprotection and C&D to be combined in a single step. This reduces solvent consumption, processing time, and CNET levels. Additionally, we showed that substitution of piperazine for triethylamine in the phosphorus deprotection step of supported-synthesis leads to reduced reaction times and lower levels of CNET impurities.

求助全文

通过发布文献求助，成功后即可免费获取论文全文。去求助

来源期刊

Nucleic acid therapeutics BIOCHEMISTRY & MOLECULAR BIOLOGY-CHEMISTRY, MEDICINAL

CiteScore

7.60

自引率

7.50%

发文量

审稿时长

>12 weeks

期刊介绍： Nucleic Acid Therapeutics is the leading journal in its field focusing on cutting-edge basic research, therapeutic applications, and drug development using nucleic acids or related compounds to alter gene expression. The Journal examines many new approaches for using nucleic acids as therapeutic agents or in modifying nucleic acids for therapeutic purposes including: oligonucleotides, gene modification, aptamers, RNA nanoparticles, and ribozymes.