磺酸化和羧酸化环糊精的合成及其对药物分子的选择键合

Molecular recognition and multicomponent assembly based on cyclodextrin (CD) derivatives is an essential part in the field of supramolecular chemistry. Compared to the mono-modified CD derivatives, it is found that the ones possessing multiple substituents have better binding abilities. In this proposal, we would like to design and synthesize some novel sulfonated and carboxylated CDs with certain chemical composition and configuration, including the negatively charged CD compounds with the flexible alkyl chains, triazole, and aromatic groups. Moreover, the geometrical changes upon complexation with a series of drug molecules, such as the anti-cancer drugs of cisplatin, topotecan, and doxorubicin, the neuromuscular blocking agents of gallamine, tubocurarine, and cisatracurium, as well as the alkaloids of berberine and sanguinarine, will be systematically investigated by the modern analytical methods. The binding mode and stability in these supramolecular complexes will be quantitatively studied by changing the concentration, pH, and the number and type of functional groups, and the structure-activity relationship will also be discussed from the view point of thermodynamics and kinetics. Meanwhile, the synergetic effect and molecular recognition mechanism arising from the non-covalent forces, including the hydrophobic, electrostatic, and dipole interactions, will be comparatively explored with the native CD and mono-modified derivatives as references. We also envision that the present study will continue to energize the development of supramolecular chemistry.

环糊精的分子识别与组装是超分子化学的一项重要研究内容，而多取代环糊精较之单修饰环糊精具有更好的键合能力。因此，该项目拟设计和合成新颖的结构确定的羧酸化和磺酸化环糊精，包括含有不同长度的柔性烷基链、三唑基和其它芳香基团的电负性环糊精衍生物，采用现代测试技术手段确定其构型，研究该类主体化合物与药物分子（如顺铂、拓扑替康、阿霉素等抗癌药物，加拉明、筒箭毒碱、顺苯磺阿曲库铵等神经麻醉剂，以及黄连素、血根碱等生物碱）选择键合的热力学和动力学性质，并通过改变体系的浓度、温度、pH值以及修饰基团的种类和数目，考察分子的键合行为，从热力学和动力学的角度阐述分子识别的机理以及结构与功能之间的关系。同时，采用未修饰的天然环糊精和单修饰环糊精作为参照进行对比实验，考察疏水、静电和偶极等非共价相互作用在分子识别过程中的协同效应。这对于超分子化学的发展具有重要的科学意义。

根据项目申请书的要求，我们设计并合成了几类单修饰和全修饰的环糊精衍生物，其中包括羧酸化的β-环糊精；氨基酸及其衍生物修饰的β-环糊精；以及药物分子修饰的β-环糊精等。采用核磁滴定等测试技术确定了主‒客体复合物的构型，通过紫外、荧光光谱和等温量热滴定实验全面考察了该类环糊精与多种客体分子，包括二茂铁、胆酸、偶氮苯等的分子识别、超分子组装和光物理性质，并进一步阐述了它们之间的分子诱导聚集行为及其潜在的生物应用功能。研究发现，小口端全修饰的羧酸化环糊精可以诱导两亲性客体分子之间形成稳定的二元超分子纳米粒子，该纳米粒子可以有效负载抗癌药物分子；另外，我们开发了一系列脱羧化氨基酸修饰的β-环糊精衍生物，通过细胞和动物实验考察了它们对于体内有毒物质的清除能力；在此基础上，我们还利用环糊精和偶氮苯之间的光控可逆键合作用，在分子水平上调控了蛋白间的聚集和解聚行为。这些研究成果这对于具有设计和制备新型环糊精生物功能超分子组装体具有重要意义。