Incorporation of a Tethered Alcohol Enables Efficient Mechanically Triggered Release in Aprotic Environments

Abstract

Polymers that release small molecules in response to mechanical force are promising for a wide variety of applications. While offering a general platform for mechanically triggered release, previous mechanophore designs based on masked 2-furylcarbinol derivatives are limited to polar protic solvent environments for efficient release of the chemical payload. Here, we report a masked furfuryl carbonate mechanophore incorporating a tethered primary alcohol that enables efficient release of a hydroxycoumarin cargo in the absence of a protic solvent. Density functional calculations also implicate an intramolecular hydrogen bonding interaction between the tethered alcohol and the carbonyl oxygen of the carbonate that reduces the activation barrier for carbonate fragmentation leading to molecular release. This new mechanophore design expands the generality of the masked 2-furylcarbinol platform for mechanically triggered release, enabling the implementation of this strategy in a wider range of chemical environments.

Incorporation of a self-immolative spacer enables mechanically triggered dual payload release

“…24 Over the past several years, our group has developed a versatile mechanophore platform enabling the mechanically triggered release of functionally diverse small molecules that relies on masked 2-furylcarbinol derivatives. [25][26][27][28] Upon mechanochemical activation, the furan-maleimide mechanophore undergoes a formal retro-Diels-Alder reaction to reveal a thermally unstable 2-furylcarbinol derivative, which then spontaneously decomposes to release its covalently bound cargo. This general mechanophore design exhibits excellent selectivity and is capable of efficiently releasing a wide range of molecular payloads.…”

Ultrasound-Controlled Prodrug Activation: Emerging Strategies in Polymer Mechanochemistry and Sonodynamic Therapy

“…A fluorogenic hydroxycoumarin served as a model payload for facile characterization of molecular release. In their subsequent studies, Robb and colleagues constructed a library of structurally diverse furan-maleimide mechanophores (Figure b) and broadened the range of possible cargo types, including alcohol, phenol, alkylamine, arylamine, carboxylic acid, and sulfonic molecules. − These initial studies established a general platform that can be extended for ultrasound-controlled prodrug activation, leveraging the mechanical impact of ultrasound waves. However, the 20-kHz ultrasonication conditions used in these standard mechanochemistry experiments are generally considered as not suitable for biomedical applications.…”

Bioorthogonal chemistry for prodrug activation in vivo

“…162 Robb and coworkers developed a series of furan-maleimide Diels-Alder (DA) adducts that undergo ultrasound-induced retro-[4+2] cycloaddition reactions, revealing reactive 2-furylcarbinol derivatives capable of spontaneous decomposition to release covalently bound cargos under mild conditions. [163][164][165][166] In the model reaction, fluorogenic hydroxycoumarin and aminocoumarin payloads are conjugated to the furan-maleimide mechanophore through carbonate and carbamate linkers (Fig. 20).…”