Cucurbit[n]urils (CB[n]s, n = 5-8, 10, 13-15), a new family of pumpkin-shaped macrocyclic molecules, have emerged and earned significant attention in recent years. Within the CB[n]s, CB[7] has attracted the most attention owing to its superior solubility in water and appropriate size that can form complexes with numerous guest molecules of biomedical interest. In this study, we investigated the use of CB[7] for molecular encapsulation of arecoline hydrobromide (AH), camptothecin (CPT) and small-molecule kinase inhibitor (SMKI) – sorafenib (SO), and the associated benefits of such encapsulation of these compounds via in vitro and in vivo models. From our results, all these guests we mentioned above formed 1:1 host-guest complex with CB[7] with relatively high binding constant Ka. The hepatotoxicity of AH was significantly alleviated (up to 4 times) upon its encapsulation by CB[7]. Moreover, CPT@CB[7] complex exhibited reduced nonspecific toxicities with well-preserved anti-cancer activity, when compared with the free CPT. As for SO, the encapsulation of SO by a CB[7] alleviated its inherent cardiotoxicity, as demonstrated with an in vivo zebrafish model, without affecting the anti-cancer activity of the drugs. These discoveries may lead to a novel pharmaceutical formulation for improved safety of some drugs. In addition, toxicity profile of hemimethyl-substituted cucurbit[7]uril (HMeCB[7]), a derivative of CB[7] has been investigated in this study with both in vivo and a relevant in vitro cellular model. According to our results, HMeCB[7] has negligible developmental toxicity at concentrations up to 3.2 mM and very moderate cardiotoxicity and hepatotoxicity at concentrations of >0.8 mM, and is thus generally less toxic than the parent CB[7]. Our studies demonstrate that CB[7] may work as a functional pharmaceutical excipient and provide new insights into novel formulation of drugs for their side-effects and suggest that HMeCB[7] may be a promising candidate of excipient in medicinal and pharmaceutical research fields.

葫蘆脲(cucurbit[n]urils,簡稱 CB[n]s）是一類形狀類似南瓜的新型大環化合物， 在超分子化學研究中顯示出極其重要的地位和發展前景。在葫蘆脲家族中，葫 蘆脲[7]（CB[7]）由於其本身較好的水溶性和具有優秀的主客體識別能力的大 小合適的空腔，近年來已經成為熱門研究領域。 本文中採用 1H NMR，ESI-MS，紫外光譜，熒光光譜和等溫滴定量熱法考察了 以葫蘆脲[7]為主體，分別以檳榔堿(AH)，喜樹堿(CPT)和小分子激酶抑制劑索 拉菲尼(SO)為客體時，主客體分子的相互作用關係，探討主客體作用點及結合 比；同時考察了與葫蘆脲[7]形成主客體複合物后，對客體分子毒副作用以及原 有的活性作用的影響。研究結果證明本文中選擇的課題分子均能夠與葫蘆脲[7] 形成穩定的 1:1 主客體複合物。AH@CB[7]複合物相比于 AH，表現出明顯降低 的肝細胞毒性 ；CPT@CB[7]複合物在保留原有的抗癌活性的同時，CPT 本身的 非特異性毒性得到顯著緩解；另外，對於小分子激酶抑制劑，在與葫蘆脲[7]形 成複合物后，SO 的抗癌活性並沒有收到影響，而心臟毒性顯著降低。綜上，葫 蘆脲[7]與活性客體分子形成的主客體複合物展現出優秀的穩定性以及顯著改善 的生物活性。 此外，我們對葫蘆脲[7]的衍生物半甲基化-葫蘆脲[7](HMeCB[7])的生物毒性進 行了研究。結果證明 HMeCB[7]表現出非常低的毒性且具有良好的生物相容性。 我們的研究證明葫蘆脲[7]能夠作為一種新型的藥劑學輔料進行研究，並且為改 善藥物的理化性質以及降低毒副作用提供了一條新思路。另外，其衍生物半甲 基化-葫蘆脲[7]也被證明是一種很有潛力的藥用輔料。