ortho-Methoxyphenols as Convenient Oxidative Bioconjugation Reagents with Application to Site-Selective Heterobifunctional Cross-Linkers
ortho-Methoxyphenols as Convenient Oxidative Bioconjugation Reagents with Application to Site-Selective Heterobifunctional Cross-Linkers
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DOI：
10.1021/jacs.6b12966
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发表时间：
2017-03-15
影响因子：
15
通讯作者：
Francis, Matthew B.
中科院分区：
文献类型：
--
作者：
ELSohly, Adel M.;MacDonald, James I.;Francis, Matthew B.
近年来，生物分子化学选择性修饰方法的发展极大地促进了复杂蛋白质生物缀合物的合成。邻氨基苯酚或邻苯二酚与苯胺官能团的氧化偶联是化学选择性的、温和的和快速的;然而，富电子芳族化合物的氧化敏感性和商业来源的缺乏对这些反应策略的普遍使用构成了一些障碍。在此，我们确定邻甲氧基苯酚作为空气稳定的，市售的苯胺衍生物，进行有效的氧化偶联与苯胺在选择性存在的高碘酸盐作为氧化剂。机制的考虑通知的预氧化协议，可以大大减少有效耦合所需的高碘酸盐的量的发展。这些试剂的稳定性和多功能性通过使用包含邻甲氧基苯酚和2-吡啶甲醛部分的位点选择性异双功能交联剂合成复杂蛋白质蛋白质生物缀合物来证明。这种化合物用于将表皮生长因子与无基因组的MS 2病毒衣壳连接，提供可以靶向多种癌细胞类型的纳米级递送载体。
The synthesis of complex protein-based bioconjugates has been facilitated greatly by recent developments in chemoselective methods for biomolecular modification. The oxidative coupling of oaminophenols or catechols with aniline functional groups is chemoselective, mild, and rapid; however, the oxidatively sensitive nature of the electron-rich aromatics and the paucity of commercial sources pose some obstacles to the general use of these reactive strategies. Herein, we identify o-methoxyphenols as air-stable, commercially available aniline derivatives that undergo efficient oxidative couplings with anilines in selective the presence of periodate as oxidant. Mechanistic considerations informed the development of a preoxidation protocol that can greatly reduce the amount of periodate necessary for effective coupling. The stability and versatility of these reagents was demonstrated through the synthesis of complex protein protein bioconjugates using a site-selective heterobifunctional cross-linker comprising both o-methoxyphenol and 2-pyridinecarboxaldehyde moieties. This compound was used to link epidermal growth factor to genome-free MS2 viral capsids, affording nanoscale delivery vectors that can target a variety of cancer cell types.