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

Abstract

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.

Mechanistic Studies of the Photoinduced Quinone Trimethyl Lock Decaging Process

“…Figure 1 shows two variants of the well-established trimethyl lock system. [2][3][4] Either reducing a quinone or revealing a phenol produces a nucleophile that can exploit the remarkable rate enhancements associated with the trimethyl lock system, releasing HX as a generic alcohol, amine, thiol, or phosphate. Of course, deprotection of the phenol can be accomplished photochemically using established caging groups, 5,6 but this approach does not lead naturally to longer wavelength systems.…”

A Tribute to Ronald T. Borchardt—Teacher, Mentor, Scientist, Colleague, Leader, Friend, and Family Man

“…That Ron's and Dr. Cohen's "trimethyl-lock" publications were truly pioneering is beautifully articulated in a Perspective article published recently by Michael Levine and Ronald Raines. 11 Quoting from the article, Levine and Raines say the following about the "trimethyl lock": "The Trimethyl lock has been employed in chemical, biological and pharmacological contexts, providing exceptional stability of conjugates until initiation of a designated reaction triggers rapid scission. The trimethyl lock is a readily accessible and highly adaptable module.…”

“…The breadth of its demonstrated utility has been remarkable." 11 In the process of his pioneering research on the "trimethyl lock" at the NIH, Ron strengthened his skills in measuring and interpreting kinetic data, tools that would later serve him well in his penetration of the fields of prodrugs and the stability of peptides and proteins later in his career.…”

“…Other investigators have also applied the "trimethyl lock" promoiety and similar concepts to make prodrugs of anticancer agents (e.g., daunorubicin, ganciclovir, taxol) as well as fluorogenic probes. 11 Ron's group and others have utilized the cyclic peptide prodrug concept to improve oral delivery of antithrombic agents (RGD peptides and peptidomimetics). [208][209][210][211][212] Finally, the "trimethyl lock" concept has also been utilized in cleavable linkers or protecting groups in the solid-phase synthesis of peptides and oligonucleotides.…”

“…[208][209][210][211][212] Finally, the "trimethyl lock" concept has also been utilized in cleavable linkers or protecting groups in the solid-phase synthesis of peptides and oligonucleotides. 11 The above provides a brief summary and not an in-depth review of Ron's contributions over the past 25 years to the area of prodrugs of therapeutic peptides. For more details about his publications in this area, please refer to the following website: http://pharmchem.ku.edu/ronald-borchardt-0.…”