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.

中文翻译：

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揭示主客体互补在超分子单功能铂 （II） 药物中的作用


与源自顺铂的传统双功能铂 （II） 系统相比，带有平面芳香族配体的单功能铂 （II） 化合物在治疗肿瘤方面明显更有效。它们的特性可以通过使用药物载体来调节，例如，将它们捕获在大环空腔中并以受控方式释放金属药物。在这项工作中，我们引入了新的单功能铂 （II） 化合物，其一般结构为顺式-[Pt^II（NH₃）₂Cl（4-R-py）]⁺NO₃⁻ 作为吡啶铂的直接类似物，顺式-[Pt^II（NH₃）₂Cl（py）]⁺。我们研究了它们在主客体 （HG） 复合物中与葫芦[7]uril （CB7） 大环中通过水离子的化学激活。我们使用了一系列 NMR 技术来详细表征 HG 络合物，并在分子动力学 （MD） 模拟和密度泛函理论 （DFT） 计算的支持下，合理化了配体对 HG 络合物中铂中心氯化物结构和离子的影响。细胞系 A2780 和 A2780/CP 对细胞毒性和药物摄取的生物学筛选表明，具有 4-苯基吡啶和 4-五氟苯基吡啶配体的 Pt 化合物的细胞毒性与顺铂相当，并且具有 4-（1-金刚烷基）吡啶配体的 Pt 化合物的细胞毒性和药物摄取受到 CB7 载体的极大调节。 我们的观察表明 HG 复合物在未来超分子设计和生物活性的结构定制中具有巨大潜力。