Responsive Anionophores with AND Logic Multi‐Stimuli Activation

Artificial ion transport systems have emerged as an important class of compounds that promise applications in chemotherapeutics as anticancer agents or to treat channelopathies. Stimulus‐responsive systems that offer spatiotemporally controlled activity for targeted applications remain rare. Here we utilize dynamic hydrogen bonding interactions of a 4,6‐dihydroxy‐isophthalamide core to generate a modular platform enabling access to stimuli‐responsive ion transporters that can be activated in response to a wide variety of external stimuli, including light, redox, and enzymes, with excellent OFF‐ON activation profiles. Alkylation of the two free hydroxyl groups with stimulus‐responsive moieties locks the amide bonds through intramolecular hydrogen bonding and hence makes them unavailable for anion binding and transport. Triggering using a particular stimulus to cleave both cages reverses the hydrogen bonding arrangement, to generate a highly preorganized anion binding cavity for efficient transmembrane transport. Integration of two cages that are responsive to orthogonal stimuli enables multi‐stimuli activation, where both stimuli are required to trigger transport in an AND logic process. Importantly, the strategy provides a facile method to post‐functionalize the highly active transporter core with a variety of stimulus‐responsive moieties for targeted activation with multiple triggers. A modular platform for accessing stimuli‐responsive anionophores, triggered by multiple stimuli of biological relevance including light, redox, and an esterase, is reported, and accessed via post‐synthetic modification of a dynamic hydrogen bonding anionophore. By utilizing two different cages, a responsive anionophore with AND logic activation, requiring two different stimuli, was achieved.