2012/01/01 by Michael N. Levine, Ronald T. Raines · 1 citation
Biochemistry, Genetics and Molecular Biology · Chemistry · Medicine · #Acylation #Amide #Biochemistry #Cancer Treatment and Pharmacology #Catalysis #Chemical Synthesis and Analysis #Chemical biology #Chemistry #Combinatorial chemistry #Electrophile #Hydrolysis #Molecule #Nucleic acid #Organic chemistry #Stereochemistry #Steric effects #Synthetic Organic Chemistry Methods
paper · doi:10.1039/c2sc20536j
openalex publication_date 2012/01/01 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01
The trimethyl lock is an o-hydroxydihydrocinnamic acid derivative in which unfavorable steric interactions between three pendant methyl groups encourage lactonization to form a hydrocoumarin. This reaction is extremely rapid, even when the electrophile is an amide and the leaving group is an amino group of a small-molecule drug, fluorophore, peptide, or nucleic acid. O-Acylation of the phenolic hydroxyl group prevents reaction, providing a trigger for the reaction. Thus, the release of an amino group from an amide can be coupled to the hydrolysis of a designated ester (or to another chemical reaction that regenerates the hydroxyl group). Trimethyl lock conjugates are easy to synthesize, making the trimethyl lock a highly versatile module for chemical biology and related fields.