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

在化学系大分子、超分子和纳米化学计划的支持下，俄亥俄州立大学的Jovica Badjić教授致力于开发能够与包括毒素在内的各种分析物结合的新型隔离分子。花瓶状化合物(即篮子)将被制备、功能化，并使用计算和实验化学的方法来测试捕获小分子的能力。这些研究旨在扩大对包括毒素在内的特定分析物在复杂生物环境中被捕获的过程的基本理解。该计划将教育研究生、本科生和公众关于我们社会中与健康相关的中毒以及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队伍。该计划的第一个目标是研究分子篮与柱芳烃的结合。篮子-柱芳烃(BPR)杂交物的刚性、深度和定义良好的芳香性口袋旨在有利于完全包合和去溶目标生物相关的客体配体，包括烟草吡啶生物碱、兴奋剂、阿片类药物和有助于形成紧密络合物的迷幻剂。位于顶部和中部的两条官能团带被放置以产生有利的主-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的抗癌药物甲氨蝶呤的胶囊，该药物可以抑制二氢叶酸还原酶，从而干扰嘧啶的生物合成，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较深空腔篮子的内部空间。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中的变构封装，笼子的形状为截断的四面体，在角落有四个篮子。预计在狭窄的浓度窗口内发生的合作封装机制将允许在隔离毒物方面实现前所未有的控制水平。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.