Systematic Structural Tuning Yields Hydrazonyl Sultones for Faster Bioorthogonal Protein Modification.
Systematic Structural Tuning Yields Hydrazonyl Sultones for Faster Bioorthogonal Protein Modification.
复制标题
系统的结构调整产生腙磺内酯，用于更快的生物正交蛋白质修饰。
DOI：
10.1002/cbic.202300398
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Lin,Qing
中科院分区：
文献类型：
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作者：
Fang,Ming;SrikanthKumar,Gangam;Lin,Qing
报道了一系列含有邻位CF3基团、五元或六元磺内酯环和不同N-芳基取代基的肼基磺酮(HS)的合成，并表征了它们在1，3-偶极环加成反应中对双环[6.1.0]非-4-YN-9-甲醇(BCN)的水溶液稳定性和反应活性。为了避免高极性中间体的提纯，我们在合成方案中使用了两个保护基团。在优化的反应条件下，以中等到较好的产率获得了大部分HS。X-射线晶体结构分析表明，CF3中部分带负电荷的氟原子以静电的方式保护了亲电的氰亚胺(NI)中心，使其具有优异的水溶液稳定性。此外，N-芳基取代基进一步调节了HS的反应性和稳定性，富含电子的六元HS表现出良好的水溶液稳定性和增强的环加成反应活性。这些改进的HS试剂的用途是通过快速和选择性地修饰BCNK编码的纳米体，其二级速率常数高达1500 M−1s−1在磷酸盐缓冲盐水-乙醇(9 ： 1)中，这是文献中报道的最快的HS-BCN连接。
We report the synthesis of a series of hydrazonyl sultones (HS) containing an ortho‐CF3group, a five‐ or six‐membered sultone ring, and a varying N‐aryl substituent, and characterization of their aqueous stability and reactivity toward bicyclo[6.1.0]non‐4‐yn‐9‐ylmethanol (BCN) in a 1,3‐dipolar cycloaddition reaction. To avoid purification of highly polar intermediates, we employed two protecting groups in our synthetic schemes. Most HS were obtained in moderate to good yields under optimized reaction conditions. The X‐ray crystal structure analysis of two HS revealed that the partially negative‐charged fluorine atoms in CF3electrostatically shield the electrophilic nitrile imine (NI) center from a nucleophilic attack, underpinning their extraordinary aqueous stability. In addition, the N‐aryl substituents further modulate HS reactivity and stability, with the electron‐rich six‐membered HS displaying excellent aqueous stability and increased cycloaddition reactivity. The utility of these improved HS reagents was demonstrated through fast and selective modification of a BCNK‐encoded nanobody with second‐order rate constants as high as 1500 M−1s−1in phosphate‐buffered saline‐ethanol (9 : 1), representing the fastest HS–BCN ligation reported in the literature.