Vitamin B12 - Peptide Nucleic Acid Conjugates.
Vitamin B12 - Peptide Nucleic Acid Conjugates.
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维生素 B12 - 肽核酸结合物。
DOI：
10.1007/978-1-0716-1617-8_7
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Gryko,Dorota
中科院分区：
文献类型：
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作者：
Wierzba,AleksandraJ;Wojciechowska,Monika;Trylska,Joanna;Gryko,Dorota
维生素B12(钴胺，Cbl)是所有哺乳动物和一些细菌的基本营养素。从化学角度来看，它是一种高度官能化的分子，可以在多个位置连接并附着各种货物。哺乳动物和细菌细胞都为维生素B12的摄取开发了一条特定的运输途径，因此，钴胺是一种有吸引力的生物相关分子进入细胞的候选分子。事实上，结构中含有维生素B12的杂化分子已经在药物化学、诊断和生物科学中得到了广泛的应用。在这里，我们描述了合成维生素B12与肽核酸(PNA)低聚物的偶合物的合成策略。这种针对细菌DNA或RNA的短修饰寡核苷酸如果被细菌细胞有效地利用，就可以作为抗菌剂。这种寡核苷酸的摄取受到细菌细胞膜的阻碍，但维生素B12被发现能有效地将反义PNA输送到大肠杆菌和鼠伤寒沙门氏菌细胞中。这为维生素B12-PNA结合物在抗菌和诊断应用中的应用铺平了道路。维生素B12-PNA结合物可以通过铜(I)催化的叠氮-炔环加成反应(CuAAC)获得共价连接的杂交物，或者通过还原敏感的二硫键将两个构建块连接起来。这两种方法都需要通过掺入叠氮部分或通过将天然官能团转化为对硫醇起反应的部分来预先修饰维生素B12。维生素B12与PNA标记底物的偶联有效地提供了设计的偶联物。
Vitamin B12(cobalamin, Cbl) is an essential nutrient for all mammals and some bacteria. From a chemical point of view, it is a highly functionalized molecule, which enables conjugation at multiple positions and attachment of various cargoes. Both mammalian and bacterial cells have developed a specific transport pathway for the uptake of vitamin B12, and as a consequence, cobalamin is an attractive candidate for the delivery of biologically relevant molecules into cells. Indeed, hybrid molecules containing vitamin B12in their structure have found various applications in medicinal chemistry, diagnostics, and biological sciences.Herein, we describe synthetic strategies toward the synthesis of vitamin B12conjugates with peptide nucleic acid (PNA ) oligomers. Such short-modified oligonucleotides targeted at bacterial DNA or RNA can act as antibacterial agents if efficiently taken up by bacterial cells. The uptake of such oligonucleotides is hindered by the bacterial cell envelope, but vitamin B12was found to efficiently deliver antisense PNA intoEscherichia coliandSalmonellaTyphimurium cells. This paves the way to the use of vitamin B12-PNA conjugates in antibacterial and diagnostic applications.Vitamin B12-PNA conjugates can be prepared via copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) that gives access to covalently linked hybrids or via connecting both building blocks by reduction-sensitive disulfide bridge. Both approaches require prior modification of vitamin B12by incorporation of the azide moiety or via transformation of the native functional group into a moiety reactive toward thiols. Conjugation of vitamin B12with PNA-tagged substrates efficiently furnishes designed conjugates.