Host-Guest Interactions of Ruthenium(II) Arene Complexes with Cucurbit[7/8]uril

Cucurbit[n]urils (CB[n]s) have been recognized for their chemical and thermal stability, and their ability to bind many neutral and cationic guest molecules makes them excellent hosts in a range of supramolecular applications. In drug delivery, CB[n]s can enhance drug solubility, improve chemical and physical drug stability, and allow for triggered and controlled release. This study aimed to investigate the ability of CB[7] and CB[8] as molecular hosts to bind ruthenium(II) arene complexes that are current anticancer lead structures in the area of metallodrugs. Both, experimental and computational methods, led to insights into the binding preferences and geometries of [Ru^II(cym)Cl₂]₂ (1; cym = η⁶-p-cymene), [Ru^II(cym)(dmb)Cl₂]) (2; cym = η⁶-p-cymene; dmb = 1,3-dimethylbenzimidazol-2-ylidene), and [Ru^II(cym)(pta)Cl₂] (3, RAPTA-C; cym = η⁶-p-cymene; pta = 1,3,5-triaza-7-phospha-adamantane) with CB[7] and CB[8]. Competition experiments by mass spectrometry revealed clear preferences of 2 for CB[8] and 3 for CB[7]. Based on a comparison of the associated interaction energies from quantum chemical calculations as well as experimental data, 3@CB[7] clearly prefers a binding mode, where the pta ligand is located inside the cavity of the host, and the metal ion interacts with two of the carbonyl groups on the rim of CB[7]. In contrast, complex 2 binds in two different orientations with interaction energies similar to those of both CB[n]s, with the cym ligand being either inside or outside of the cavity. These findings suggest that ruthenium(II) arene complexes are able to form stable host-guest interactions with CB[n]s, which can be exploited as drug delivery vehicles in further metallodrug development to improve their chemical stability.