Design, Synthesis and Evaluation of Scaffolds for Thiol-Mediated Tunable Drug Release

Abstract

Spatiotemporal control over drug delivery is highly desirable, but challenging. In particular, limited examples of small molecule-based scaffolds for tunable drug release are known. A routinely used metabolic trigger for drug release is cysteine-containing proteins and peptides. Here, we present results of our design, synthesis and evaluation of a new thiol-activated scaffold for drug release. We designed cinnamate-based benzoate esters as prototype scaffolds for tunable drug release. These compounds were prepared using a Baylis-Hillman reaction as the first step followed by a Mitsunobu reaction to install a self-immolable 2-nitroaryl linker. This 2- nitroaryl linker was attached to benzoic acid, a model for a carboxylic acid containing drug. We provide evidence for high stability of this prototype in physiological pH in the absence of a thiol trigger but in presence of a physiological thiol entity such as glutathione, release of a carboxylic acid drug mimic was initiated. We found the prototype to have a half-life of about 8h in the presence of 1 mM glutathione. A potential advantage of this scaffold is the availability of structural handles to control rate of reaction with glutathione. The synthesis and evaluation of such modified derivatives are currently underway.