Development of a 3‿amino linker with high conjugation activity and its application to conveniently cross-link blunt ends of a duplex

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• 作者：Keiko Kowata^a ; Naoshi Kojima^b ; Yasuo Komatsu^a ; ^{komatsu-yasuo@aist.go.jp" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Amino linker ; Nucleic acids ; Oligonucleotides ; Labeling ; Cross-link ; anti-microRNA
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：1 May 2016
• 年：2016
• 卷：24
• 期：9
• 页码：2108-2113
• 全文大小：530 K

文摘

The 2-aminoethyl carbamate linker (ssH linker) exhibits high activity in modifying the 5′-termini of oligonucleotides; however, the ssH linker is not appropriate for 3′-terminal modification because it undergoes intramolecular trans-acylation under heat–aqueous ammonia conditions. We developed an N-(2-aminoethyl)carbamate linker (revH linker), in which the carbamate is oriented in the reverse direction relative to that in 2-aminoethyl carbamate. The revH linker was tolerant to heat–alkaline conditions and retained its high reactivity in conjugation with exogenous molecules. The 3′-revH linker was efficiently linked with the 5′-ssH linker at the termini of complementary double strands with a bifunctional molecule, producing a synthetic loop structure. An anti-microRNA oligonucleotide (AMO) was prepared from the chemical ligation of three-stranded 2′-O-methyl RNAs, and the AMO with two alkyl loops exhibited high inhibition activity toward miRNA function. The revH linker is not only useful for 3′-terminal modification of oligonucleotides but also expands the utility range in combination with the 5′-ssH linker.