Revealing the effect of host–guest complementarity in supramolecular monofunctional platinum(ii) drugs†

Abstract

Monofunctional platinum(II) compounds bearing planar aromatic ligands can be significantly more potent for the treatment of tumors than the traditional bifunctional platinum(II) systems derived from cisplatin. Their properties can be modulated by using a drug carrier, for example, by trapping them into a macrocyclic cavitand and releasing the metallodrug in a controlled manner. In this work, we introduce new monofunctional platinum(II) compounds with the general structure cis-[Pt^II(NH₃)₂Cl(4-R-py)]⁺NO₃⁻ as direct analogs of pyriplatin, cis-[Pt^II(NH₃)₂Cl(py)]⁺. We investigated their chemical activation by aquation in host–guest (HG) complexes with the cucurbit[7]uril (CB7) macrocycle. We used a range of NMR techniques to characterize the HG complexation in detail, and the effects of the ligand on the structure and aquation of chloride at the platinum center in the HG complexes were rationalized with the support of molecular dynamics (MD) simulations and density-functional theory (DFT) calculations. Biological screening of the cytotoxicity and the drug uptake by cell lines A2780 and A2780/CP showed that the cytotoxicity of the Pt-compound with 4-phenylpyridine and 4-pentafluorophenylpyridine ligand was comparable to that of cisplatin and that the cytotoxicity and drug uptake of the Pt-compound with a 4-(1-adamantyl)pyridine ligand was greatly modulated by the CB7 carrier. Our observations indicate great potential for HG complexes in the future supramolecular design and structural tailoring of biological activity.