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Adapting the Glaser Reaction for Bioconjugation: Robust Access to Structurally Simple, Rigid Linkers
Author(s) -
Silvestri Anthony P.,
Cistrone Philip A.,
Dawson Philip E.
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201705065
Subject(s) - bioconjugation , combinatorial chemistry , linker , generality , chemistry , ligand (biochemistry) , coupling (piping) , coupling reaction , aqueous solution , diol , copper , nanotechnology , computer science , materials science , polymer chemistry , organic chemistry , receptor , catalysis , psychology , biochemistry , metallurgy , psychotherapist , operating system
Copper‐mediated coupling between alkynes to generate a structurally rigid, linear 1,3‐diyne linkage has been known for over a century. However, the mechanistic requirement to simultaneously maintain Cu I and an oxidant has limited its practical utility, especially for complex functional molecules in aqueous solution. We find that addition of a specific bpy‐diol ligand protects unprotected peptides from Cu II ‐mediated oxidative damage through the formation of an insoluble Cu II gel which solves the critical challenge of applying Glaser coupling to substrates that are degraded by Cu II . The generality of this method is illustrated through the conjugation of a series of polar and nonpolar labels onto a fully unprotected GLP‐1R agonist through a linear 7 Å diynyl linker.