Syracuse University's Professor Xiaoran Hu: A cucurbit[7]uril–adamantane noncovalent click-to-release strategy enables a new pathway for supramolecular bioorthogonal activation.

Recently, a research team led by Professor Xiaoran Hu at Syracuse University published a groundbreaking study in Angewandte Chemie International Edition, a leading international chemistry journal. The team introduced a noncovalent click-and-release strategy based on cucurbit[7]uril-adamantane (CB[7]-Ad). Moving beyond conventional covalent conjugation, this work establishes an entirely new pathway for supramolecular bioorthogonal activation.

Research subject: cucurbit[7]uril (abbreviated as Q[7] or CB[7])

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This work establishes the first noncovalent click-and-release system based on the cucurbit[7]uril–adamantane (CB[7]-Ad) host–guest interaction, overcoming key limitations of conventional covalent approaches such as oxidation sensitivity, slow kinetics, and extensive side reactions. We designed a self-immolative guest (SIG) as a drug prodrug, with reactive sites masked upon complexation with cucurbituril. Upon addition of a high-affinity adamantane competitor, noncovalent competitive displacement triggers self-immolation and release of the active molecule, enabling reversible, on-demand delivery of bioactive species. This strategy supports a broad substrate scope and is compatible with phenolic drugs; incorporation of a p-hydroxybenzyl alcohol linker further extends its use to amine-based photosensitizers. Using methylene blue-based SIG2, we achieved controllable activation of in vitro photodynamic therapy: singlet oxygen production and HeLa cell killing occurred only upon adamantane stimulation. Cucurbit[7]uril and adamantane showed negligible cytotoxicity and excellent biocompatibility. This work expands bioorthogonal cleavage chemistry and provides a new supramolecular platform for stimuli-responsive drug delivery and functional materials.

A Noncovalent Click-to-Release Strategy for Controlling Bond Cleavage and Prodrug Activation

Fu, X.; Xu, B.; Maity, S.; Wu, M.; Westbrook, L. G.; Henderson, J. H.; Wu, Y.; Edwards, K. A.; Acharya, A.; Hu, X. Angew. Chem. Int. Ed. 2026, 65(9), e15594. https://doi.org/10.1002/anie.202515594.