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{"title":"Carbocyclic C-C Bond Formation: Intramolecular Radical Ring Closure to Yield Diastereomerically Pure (7′S-Me- or 7′R-Me-) Carba-LNA Nucleotide Analogs","authors":"Oleksandr Plashkevych, Ram Shankar Upadhayaya, Jyoti Chattopadhyaya","doi":"10.1002/cpnc.29","DOIUrl":null,"url":null,"abstract":"<p>In light of the impressive gene-silencing properties of carba-LNA modified oligo DNA and RNA, both in antisense RNA and siRNA approaches, which have been confirmed as proof-of-concept for biochemical applications in post-transcriptional gene silencing, we envision the true potential of carba-LNA modifications to be revealed soon. Herein we provide detailed protocols for synthesis of carba-LNA-A, -G, -<sup>5-Me</sup>C, and -T nucleosides on a medium/large scale (gram scale), as well as important guidelines for incorporation of these modified carba-LNAs into DNA or RNA oligonucleotides. Creation of a stereoselective C-C bond during the 5-<i>exo</i> radical intramolecular cyclization involves trapping of a C2′ radical intermediate intramolecularly by the vicinal double bond of a C4′-tethered ─CH<sub>2</sub>-CH═CH<sub>2</sub> group. All diastereomers of substituted carba-LNAs are now available in pure form. The present procedure allows carba-LNA to be commercialized for medicinal or biotechnological purposes. © 2017 by John Wiley & Sons, Inc.</p>","PeriodicalId":10966,"journal":{"name":"Current Protocols in Nucleic Acid Chemistry","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2017-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/cpnc.29","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Current Protocols in Nucleic Acid Chemistry","FirstCategoryId":"1085","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/cpnc.29","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"Chemistry","Score":null,"Total":0}
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Abstract
In light of the impressive gene-silencing properties of carba-LNA modified oligo DNA and RNA, both in antisense RNA and siRNA approaches, which have been confirmed as proof-of-concept for biochemical applications in post-transcriptional gene silencing, we envision the true potential of carba-LNA modifications to be revealed soon. Herein we provide detailed protocols for synthesis of carba-LNA-A, -G, -5-Me C, and -T nucleosides on a medium/large scale (gram scale), as well as important guidelines for incorporation of these modified carba-LNAs into DNA or RNA oligonucleotides. Creation of a stereoselective C-C bond during the 5-exo radical intramolecular cyclization involves trapping of a C2′ radical intermediate intramolecularly by the vicinal double bond of a C4′-tethered ─CH2 -CH═CH2 group. All diastereomers of substituted carba-LNAs are now available in pure form. The present procedure allows carba-LNA to be commercialized for medicinal or biotechnological purposes. © 2017 by John Wiley & Sons, Inc.
碳环C-C键形成:分子内自由基环闭合产生非对映纯(7'S-Me -或7'R-Me -)碳- rna核苷酸类似物
鉴于carba-LNA修饰寡核苷酸和RNA的令人印象深刻的基因沉默特性,无论是反义RNA还是siRNA方法,都已被证实为生物化学在转录后基因沉默中的应用概念验证,我们设想carba-LNA修饰的真正潜力将很快被揭示。本文提供了中/大规模(克级)合成碳- lna - a、-G、-5-MeC和-T核苷的详细方案,以及将这些修饰的碳- lnas整合到DNA或RNA寡核苷酸中的重要指南。在5-外显子自由基分子内环化过程中,立体选择性C-C键的形成涉及到一个C2 '自由基中间分子内被一个C4 ' -拴在一起的CH2- ch = CH2基团的邻近双键捕获。取代碳- lnas的所有非对映体现在都有纯形式。本程序允许碳水化合物rna商业化用于医药或生物技术目的。©2017 by John Wiley &儿子,Inc。
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