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

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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.