Cucurbit[n]uril binding of platinum anticancer complexes

The encapsulation of cisplatin by cucurbit7]uril (Q7]) and multinuclear platinum complexes linked via a 4,4'-dipyrazolylmethane (dpzm) ligand by Q7] and cucurbit8]uril (Q8]) has been studied by NMR spectroscopy and molecular modelling. The NMR studies suggest that some cisplatin binds in the cucurbituril cavity, while cis-PtCl(NH3)2(H2O)]+ only binds at the portals. Alternatively, the dpzm-linked multinuclear platinum complexes are quantitatively encapsulated within the cavities of both Q7] and Q8]. Upon encapsulation, the non-exchangeable proton resonances of the multinuclear platinum complexes show significant upfield shifts in 1H NMR spectra. The H3/H3* resonances shift upfield by 0.08 to 0.55 ppm, the H5/H5* shift by 0.9 to 1.6 ppm, while the methylene resonances shift by 0.74 to 0.88 ppm. The size of the resonance shift is dependent on the cavity size of the encapsulating cucurbituril, with Q7] encapsulation producing larger shifts than Q8]. The upfield shifts of the dpzm resonances observed upon cucurbituril encapsulation indicate that the Q7] or Q8] is positioned directly over the dpzm linking ligand. The terminal platinum groups of trans-{PtCl(NH3)2}2 mu-dpzm]2+ (di-Pt) and trans-trans-{PtCl(NH3)2}2-trans-{Pt(dpzm)2(NH3)2}]4+ (tri-Pt) provide a barrier to the on and off movement of cucurbituril, resulting in binding kinetics that are slow on the NMR timescale for the metal complex. Although the dpzm ligand has relatively few rotamers, encapsulation by the larger Q8] resulted in a more compact di-Pt conformation with each platinum centre retracted further into each Q8] portal. Encapsulation of the hydrolysed forms of di-Pt and tri-Pt is considerably slower than for the corresponding Cl forms, presumably due to the high-energy cost of passing the +2 platinum centres through the cucurbituril portals. The results of this study suggest that cucurbiturils could be suitable hosts for the pharmacological delivery of multinuclear platinum complexes.