自1967年C. J. Pederson发现冠醚以来，主客体化学研究的广度和深度在诸多方面取得了长足的发展，从静态研究向动态发展，从微观研究向宏观发展，从结构构建向功能组装发展。本论文沿着“结合——组装——功能”这一主线，开展了基于葫芦脲主客体化学的结合可控、组装可控和功能可控的相关研究，主要取得了三方面的成果。 一、结合可控：围绕如何精细调节协同性的基本问题，我们以葫芦[8]脲三元主客体复合为研究对象，通过设计合成一系列带有不同亲疏水侧基的客体分子，来平衡经典与非经典疏水效应，从而实现了对三元主客体复合协同性的精细调节，协同因子可以在10-3到102之间调控。调控协同性的基本逻辑是通过调节分子结构来平衡熵焓贡献，从而对非共价相互作用予以精细的控制。这项工作将为实现结合可控提供了一种一般性的研究思路。 二、组装可控：围绕如何调控超分子聚合的科学问题，我们在非共价聚合驱动力的基础上，引入调节单体刚性的非共价杠杆，建立了一种可控的自分类识别体系。通过逐渐增加单体的刚性，我们实现了对环-链平衡的控制，从而建立了一种可控超分子聚合的新方法。超分子聚合物的分子量可以在10 kDa到97 kDa之间调控。类似的方法可望推广到其他主客体化学或者可逆化学当中，也有望用于制备其他拓扑结构的超分子聚合物。 三、功能可控：围绕如何实现化疗药物降毒增效的难题，我们提出了超分子化疗的新概念。为了验证这一概念，我们通过葫芦[7]脲与二甲基紫精的主客体复合来降低其对正常细胞的毒性，同时利用肿瘤标记物精胺来竞争置换出二甲精紫精，成功地恢复其抗癌活性。更进一步地，我们将超分子化疗推广到奥沙利铂这一肠癌化疗药物上。我们运用葫芦[7]脲来包合奥沙利铂，降低其对正常细胞的毒性，而后利用肠癌标记物精胺来可控地释放奥沙利铂。更为重要的是，精胺的消耗与奥沙利铂的释放可以进一步提高其抗癌活性。基于此，我们最终确立了超分子化疗这一新的概念。超分子化疗有望推广到多种超分子主体和传统化疗药物中，为化疗领域开拓新的方向。
Since the discovery of crown ether by C. J. Pederson in 1967, the breadth and depth of research on host-guest chemistry has been significantly developed in many aspects. It moves forward from static to dynamic research, from microscopic to macroscopic level, and from structural architectures to functional assemblies. Along a line of “association--assembly--function”, this thesis concerns controllable association, controllable assembly and controllable function. Three main achievements are summarized as follows. (1) Controllable association: to answer a basic question about how to precisely control binding cooperativity, cucurbit[8]uril-mediated ternary host-guest complexation was selected as our research objective. We designed and synthesized a series of guest molecules with different hydrophilic and hydrophobic side groups for balancing classical and non-classical hydrophobic effect behind this association. In this way, we realize precise control over binding cooperativity behind this ternary host-guest complexation, of which the cooperative parameter can be well tuned from 10-3 to 102. The basic logic of controlling cooperativity is to manipulate non-covalent interactions by tuning molecular structures for balancing entropy and enthalpy in an elegant way. This work may provide a general strategy for tailoring controllable associations. (2) Controllable assembly: to solve a scientific question about how to realize control over supramolecular polymerization, we introduced a controllable self-sorting system among a non-covalent driving force for polymerization and a non-covalent lever to control the rigidity of monomers. Through self-sorting, the ring-chain equilibrium behind supramolecular polymerization can be well controlled by gradually controlling the rigidity of monomers. In this way, a new method for controllable supramolecular polymerization is developed, of which the molecular weight of supramolecular polymer can be well tuned from 10 kDa to 97 kDa. Similar methodologies can be extended to other host-guest chemistry or reversible chemistry for fabricating supramolecular polymers with tailor-made structures and topologies. (3) Controllable function: to tackle a practical problem about how to improve chemotherapeutic drugs, we presented a new concept of supramolecular chemotherapy. As a proof of concept, we utilized host-guest complexation between cucurbit[7]uril and dimethyl viologen for decreasing its cytotoxicity to normal cells. And with the aid of a tumor cancer biomarker, spermine, dimethyl viologen can be competitively replaced from host cavity, thus sucessfully recovering its anticaner biaoactivty. Furthermore, we extended supramolecular chemotherapy to oxaliplatin, which is a chemotherapeutic drug for colorectal cancer. We empolyed cucurbit[7]uril to encapsulate oxaliplatin for reducing tis cytotoxicity to normal cells, and controlled release of oxaliplatin can be also achieved through competitive replacement by spermine. More importantly, the release of oxaliplatin and consumption of spermine can further result in the enhanced anticancer bioactivity. In this way, we finally established this new concept of supramolecular chemotherapy. Supramolecular chemotherapy could be extended to various supramolecular hosts and traditional chemotherapeutic drugs, thus opening a new horizon for the realm of chemotherapy.
