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

葫芦宿主对水中生物和药用客体的选择性分子识别

• 批准号: RGPIN-2015-06810
• 负责人: Macartney, Donal
• 金额: $ 1.46万
• 依托单位: Queen's University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=614373
• 关键词: Selective; Molecular; Recognition; Biological; Medicinal

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.

我建议的研究计划包括继续研究葫芦[n]脲（CB[n]，n = 5- 8，10，14）主体分子与生物和医学利益的客人的超分子主客体复合物（其他分子内的分子）。这项工作将提供一个更好的理解弱的非共价力控制的客体分子在水中的选择性分子识别，考虑CB[n]作为药物递送和释放，药物逆转，疾病生物标志物的识别，以及补救药物和代谢产物的潜在应用对水生生态有毒。环状CB[n]主体由通过两个收缩极性入口进入的疏水腔组成。CB[7]主体特别是在水中与客体形成非常稳定的复合物，这些复合物可以在每个开口处放置正电荷并填充内部空腔，使得所有“高能”水分子被取代。 生物学和医学感兴趣的分子上的正电荷是普遍存在的，并且通常用于提供由其他分子（包括受体蛋白质）的选择性识别。（基态）和PKa*（激发态）值（酸强度）增加CB[n]主体内的质子化客人，正在进行的研究集中在通过同时控制阳离子芳香族染料客体的吸收和发射特性来选择性调节宿主和酸浓度。这些客体中的一些表现为激发态pKa* < 0的“超级”光酸，并且它们的吸收和发射光谱随着CB的添加而显著改变[7]（因此可能用作测定的客体）。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，所有这些都在生理pH水平下质子化。 迄今为止，在CB[n]主体中包含中性客体的研究很少。我们将研究非环状和环状醚（有用的燃料含氧化合物，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复合物。该研究还将包括研究CB[7]主客体复合物形成和解离的速度，使用NMR和常规和停流吸收和发射方法，与中性和阳离子客体。机械感兴趣的功能包括收缩门户的作用和简单的阳离子的能力，以“帽”这些门户网站，和介质的影响，如pH值。CB[n]的捕获和释放这些客人的动力学和机制的理解是重要的，在上述潜在的应用。该研究计划将在超分子化学的跨学科领域提供高素质的化学家的优秀培训，以在学术或工业研究中产生未来的影响。