Investigating the Proteome Reactivity and Selectivity of Aryl Halides

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• 作者：D. Alexander Shannon ; Ranjan Banerjee ; Elizabeth R. Webster ; Daniel W. Bak ; Chu Wang ; Eranthie Weerapana
• 刊名：Journal of the American Chemical Society
• 出版年：2014
• 出版时间：March 5, 2014
• 年：2014
• 卷：136
• 期：9
• 页码：3330-3333
• 全文大小：303K
• 年卷期：v.136,no.9(March 5, 2014)
• ISSN：1520-5126

文摘

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_NAr) 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.