Selective Molecular Recognition of Biological and Medicinal Guests in Water by Cucurbit[n]uril Hosts

我提出的研究计划包括继续研究瓜环(CB[n]，n=5-8，10，14)与具有生物学和药用价值的客体的超分子主客体复合体(其他分子内的分子)。这项工作将更好地了解支配水中客体分子选择性分子识别的弱非共价力，并考虑CB[n]作为宿主在药物输送和释放、药物逆转、疾病生物标志物识别以及修复对水生态有毒性的药物和代谢物方面的潜在应用。环状CB[n]宿主由一个疏水空腔组成，该空腔通过两个收缩的极口进入。尤其是CB[7]主人与客人在水中形成了非凡而稳定的络合物，这些络合物可以在每个开口处放置正电荷，并填充内部空腔，从而使所有“高能”水分子被置换。 具有生物和医药价值的分子上的正电荷是普遍存在的，通常用于提供包括受体蛋白在内的其他分子的选择性识别。在CB[n]宿主中，客体的pKA(基态)和pKA*(激发态)值(酸强度)会增加，正在进行的研究集中在通过同时控制主体和主体的酸浓度来选择性地调节客体的阳离子芳香族染料的吸收和发射性能。其中一些客体表现为具有激发态pKa*&lt；0的超级光酸，其吸收光谱和发射光谱随着CB[7]的加入而显著改变(因此作为客体可能对分析很有用)。我们还将继续研究含有碱性氮官能团的药物分子的选择性络合，所有这些都是在生理pH水平下质子化的。 到目前为止，关于CB[n]主体中包含中性客体的调查很少。我们将继续研究酰基和环醚(有用的燃料含氧物，但对环境有害)和胺硼烷(储氢材料)，它们与CB[7]在水中形成相对稳定的主客体络合物。这项研究还将包括使用核磁共振以及常规和停流吸收和发射方法研究CCB[7]主客体络合物与中性和阳离子客体形成和解离的速度。机械特性包括收缩通道的作用和简单阳离子“封闭”这些通道的能力，以及介质效应，如pH。了解CB[n]捕获和释放这些客体的动力学和机理对于上面列出的潜在应用非常重要。该研究计划将为超分子化学跨学科领域的高素质化学家提供出色的培训，以便在未来的学术或工业研究中产生影响。

My proposed research program involves continuing investigations of supramolecular host-guest complexes (molecules inside other molecules) of the cucurbit[n]uril (CB[n], n = 5-8,10,14) host molecules with guests of biological and medicinal interest. The work will provide a better understanding of the weak non-covalent forces governing the selective molecular recognition of guest molecules in water, with a consideration of potential applications of CB[n] as hosts for drug delivery and release, drug reversal, the recognition of disease biomarkers, and remediation of drugs and metabolites which are toxic to the aquatic ecology. The cyclic CB[n] hosts are comprised of a hydrophobic cavity accessed through two constrictive polar portals. The CB[7] host in particular forms extraordinary stable complexes in water with guests which can position positive charges at each opening and fill the internal cavity such that all of the ‘high energy’ water molecules are displaced. Positive charges on molecules of biological and medicinal interest are ubiquitous and often serve to provide selective recognition by other molecules including receptor proteins.  The guest pKa (ground state) and pKa* (excited state) values (acid strength) increase for protonated guests within CB[n] hosts, and ongoing studies are focussed on selective tuning of absorption and emission properties of cationic aromatic dye guests by simultaneous controls of host and acid concentrations. Some of these guests behave as a “super” photoacid with an excited state pKa* < 0, and their absorption and emission spectra change significantly with addition of CB[7] (thus are potentially useful as guests for assays). We will also continue our studies on the selective complexations of drug molecules containing basic nitrogen functional groups, all of which are protonated at physiological pH levels. There have been few investigations to date on the inclusion of neutral guests in CB[n] hosts.  We will investigate acylic and cyclic ethers (useful fuel oxygenates, but harmful to the environment), and amine boranes (hydrogen storage materials), which form relatively stable host-guest complexes with CB[7] in water. The research will also include studies on how fast the CB[7] host-guest complexes form and dissociate, with neutral and cationic guests, using NMR and conventional and stopped-flow absorption and emission methods. Features of mechanistic interest include the role of the constrictive portals and the ability of simple cations to “cap” these portals, and medium effects such as pH. An understanding of the kinetics and mechanisms of the capture and release of these guests by CB[n] is important in the potential applications listed above. The research program will provide excellent training of highly qualified chemists in the interdisciplinary field of supramolecular chemistry to have future impact in academic or industrial research.