Acyclic cucurbituril featuring pendant cyclodextrins

Acyclic cucurbit[n]uril-beta-cyclodextrin chimeric host H1 is presented. The goal of the study is to deepen the cavity of the receptor to allow beta-CD complexation of moieties on the guest (especially fentanyl) that protrude from the cavity to enhance binding affinity and deliver new supramolecular antidotes for fentanyl intoxication. H-1 NMR spectroscopy was used to deduce the geometry of the complexes between H1 and H2 and the guest panel whereas isothermal titration calorimetry was used to determine the thermodynamic parameters of complexation. Hosts H1 and H2 retain the essential molecular recognition features of CB[n] receptors, but H1 binds slightly stronger towards the guest panel than H2. Compared to tetraanionic M1 and M2, dianionic H1 and H2 are less potent receptors which reflects the importance of electrostatic interactions in this series of hosts. The work highlights the challenges inherent in the optimisation of binding affinity of hosts as potential supramolecular antidotes.