A tunable stimuli-responsive module based on an α-hydroxymethyl-α,β-unsaturated carbonyl scaffold

Abstract

The α-hydroxymethyl-α,β-unsaturated carbonyl (HMUC) scaffold represents a valuable framework for constructing nucleophile-responsive materials. However, nucleophiles are largely limited to thiols and amines. Given the ubiquity of thiols and amines in biological systems, this limitation hinders the creation of materials that can be selectively activated by exogenous stimuli. By tuning the electron density of the double bond and assessing its reactivity with various nucleophiles, we present here the discovery of the N-ethyl-2-(hydroxymethyl)acrylamide (NEHMAA) scaffold as a versatile building block for fabricating exogenous stimuli-responsive materials. The selenol species 4-cyanobenzylselenol (from its precursor bis(4-cyanobenzyl)diselenide, Se4) effectively activates NEHMAA-decorated “caged” molecules. Furthermore, the NEHMAA unit was employed to prepare prodrugs, and Se4-dependent cytotoxicity of these prodrugs was observed in cancer cells. The orthogonal reactivity between the NEHMAA unit and Se4 enriches the existing repertoire for constructing exogenous stimuli-responsive smart materials.