Trimethyl lock: a trigger for molecular release in chemistry, biology, and pharmacology

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...

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Bibliographic Details
Published in:Chemical science (Cambridge) 2012-01, Vol.3 (8), p.2412-242
Main Authors: Levine, Michael N, Raines, Ronald T
Format: Article
Language:English
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Summary: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. The trimethyl lock provides unmatched attributes as a trigger for the release of small molecules by an enzymatic, chemical, or photolytic process.
ISSN:2041-6520
2041-6539
DOI:10.1039/c2sc20536j