Pillararene-Basket Conjugates, Deeper Cavity Baskets and Covalent Basket Cages for Allosteric Complexation of Toxicants

用于毒物变构络合的柱芳烃篮缀合物、深腔篮和共价篮笼

• 批准号: 2304883
• 负责人: Jovica Badjic
• 金额: $ 52.19万
• 依托单位: Ohio State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2304883&HistoricalAwards=false
• 关键词: Pillararene; Basket; Conjugates; Deeper; Cavity

With support from the Macromolecular, Supramolecular and Nanochemistry (MSN) Program in the Division of Chemistry, Professor Jovica Badjić at Ohio State University aims to develop novel sequestering molecules capable to binding to a variety of analytes includes toxins. Vase-shaped compounds (i.e., baskets) are to be prepared, functionalized, and tested for trapping small molecules using methods of both computational and experimental chemistry. These studies are aimed to broaden fundamental understanding about the process by which specific analytes, including toxins, can be captured in complex biological environment. The program will educate graduate, undergraduate students, and public about health-related intoxications in our society and ways to use supramolecular chemistry to address them. The interdisciplinary research training to be provided to students will help to prepare a skilled workforce for the chemical industry or academia.The first objective of the program is to examine conjugation of molecular baskets to pillararenes. A rigid, deep, and well-defined aromatic pocket of basket-pillararene (BPr) hybrids is designed to favor a full inclusion and desolvation of targeted biologically relevant guest ligands, including tobacco pyridine alkaloids, stimulants, opioids, and hallucinogens contributing to the formation of tight complexes. Two belts of functional groups, at the top and in the middle, are positioned to generate favorable host-guest contacts to improve stability and binding selectivity. The second objective of the program is to learn about encapsulation of the potent anticancer drug, methotrexate, that inhibits dihydrofolate reductase, thereby interfering with pyrimidine biosynthesis, and hence DNA replication. This sizeable and negatively charged compound is expected to fold and thus complement the inner space of deeper cavity baskets holding negative carboxylates. The third objective of the program is to develop allosteric encapsulation of four anti-cancer drugs within water-soluble covalent basket cages, having the shape of a truncated tetrahedron with four baskets at the corners. A projected mechanism of cooperative encapsulation occurring over a narrow concentration window is anticipated to permit an unprecedented level of control in the sequestration of toxicants.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

在化学系大分子，超分子和纳米化学（MSN）计划的支持下，俄亥俄州州立大学的Jovica Badjić教授旨在开发能够结合各种分析物（包括毒素）的新型螯合分子。花瓶状化合物（即，篮）被制备、官能化并使用计算和实验化学方法测试用于捕获小分子。这些研究旨在扩大对特定分析物（包括毒素）在复杂生物环境中捕获过程的基本理解。该计划将教育研究生，本科生和公众有关健康相关的中毒在我们的社会和如何使用超分子化学来解决这些问题。 为学生提供的跨学科研究培训将有助于为化学工业或学术界培养一支熟练的劳动力。该计划的第一个目标是研究分子篮与柱芳烃的结合。篮柱芳烃（BPr）杂合体的刚性，深，和明确的芳香口袋的设计有利于充分包容和去溶剂化的目标生物相关的客体配体，包括烟草吡啶生物碱，兴奋剂，阿片类药物，和致幻剂有助于形成紧密的复合物。位于顶部和中间的两个官能团带被定位成产生有利的主客体接触，以提高稳定性和结合选择性。该计划的第二个目标是了解有效抗癌药物甲氨蝶呤的封装，甲氨蝶呤抑制二氢叶酸还原酶，从而干扰嘧啶生物合成，从而干扰DNA复制。这种相当大的带负电荷的化合物预计会折叠，从而补充容纳负羧酸盐的更深腔篮的内部空间。该计划的第三个目标是开发四种抗癌药物在水溶性共价篮笼内的变构包封，其具有在角处具有四个篮的截顶四面体的形状。预计在一个狭窄的浓度窗口发生的合作封装机制，预计允许在有毒物质的封存控制前所未有的水平。该奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。