Your mother was right, washing matters: An alkyne-analog of ibuprofen reveals unwanted reactivity of aromatic compounds with proteins during copper-catalyzed click chemistry. (15th September 2021)

• Record Type: Journal Article
• Authors: Cutolo, Giuliano; Shankar, Sahiti N.; Pratt, Matthew R.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 48(2021)
• Publication Date: 2021-09-15
• Subjects: Bioorthongonal chemistry -- Click chemistry -- Ibuprofen -- Protein labeling; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2021.128260
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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.