Department of Chemistry, Merkert Chemistry Center , Boston College, Chestnut Hill, Massachusetts 02467, United States.
J Am Chem Soc. 2014 Mar 5;136(9):3330-3. doi: 10.1021/ja4116204. Epub 2014 Feb 24.
Protein-reactive electrophiles are critical to chemical proteomic applications including activity-based protein profiling, site-selective protein modification, and covalent inhibitor development. Here, we explore the protein reactivity of a panel of aryl halides that function through a nucleophilic aromatic substitution (S(N)Ar) mechanism. We show that the reactivity of these electrophiles can be finely tuned by varying the substituents on the aryl ring. We identify p-chloro- and fluoronitrobenzenes and dichlorotriazines as covalent protein modifiers at low micromolar concentrations. Interestingly, investigating the site of labeling of these electrophiles within complex proteomes identified p-chloronitrobenzene as highly cysteine selective, whereas the dichlorotriazine favored reactivity with lysines. These studies illustrate the diverse reactivity and amino-acid selectivity of aryl halides and enable the future application of this class of electrophiles in chemical proteomics.
蛋白反应性亲电试剂对于化学蛋白质组学应用至关重要，包括基于活性的蛋白质谱分析、选择性蛋白质修饰和共价抑制剂开发。在这里，我们研究了一组通过亲核芳香取代（S（N）Ar）机制起作用的芳基卤化物的蛋白反应性。我们表明，通过改变芳环上的取代基，可以精细调节这些亲电试剂的反应性。我们发现对氯-和氟硝基苯以及二氯三嗪在低微摩尔浓度下可作为共价蛋白质修饰剂。有趣的是，在复杂蛋白质组中研究这些亲电试剂的标记部位，发现对氯硝基苯对半胱氨酸具有高度选择性，而二氯三嗪则有利于与赖氨酸反应。这些研究说明了芳基卤化物的反应性和氨基酸选择性的多样性，并为该类亲电试剂在化学蛋白质组学中的未来应用奠定了基础。
