Your mother was right, washing matters: An alkyne-analog of ibuprofen reveals unwanted reactivity of aromatic compounds with proteins during copper-catalyzed click chemistry

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:48

Article

Cutolo, Giuliano¹  Shankar, Sahiti N.¹  Pratt, Matthew R.^1,2 

[1] Univ Southern Calif, Dept Chem, Los Angeles, CA 90089 USA

[2] Univ Southern Calif, Dept Biol Sci, Los Angeles, CA 90089 USA

关键词: Bioorthongonal chemistry;    Click chemistry;    Ibuprofen;    Protein labeling;   

DOI  :  10.1016/j.bmcl.2021.128260

来源: Elsevier

【 摘 要 】

Bioorthogonal chemistry, in particular the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC), has enabled the robust identification of covalent protein targets of probes and drugs. Ibuprofen is commonly used pain and fever reducer and is sold as an enantiomeric racemate. Interestingly, the stereoisomers can be enzymatically converted through an ibuprofen-CoA thioester intermediate, which might non-specifically react with protein nucleophiles. Here, we use an alkyne-analog of ibuprofen to make two discoveries. First, we find that ibuprofen likely does not result in notable chemical labeling of proteins. However, we secondly find that aromatic compounds can react with proteins during the CuAAC reaction unless they are appropriately washed out of the mixture. This second discovery of false positive labeling has important technical implications for the application of this approach.

【 授权许可】

Free