Stereo and Chemoselective Inclusion Complexations by Chiral Pillararenes and Ultra-Deep Molecular Baskets in Water

The proposed work aims to improve fundamental understanding about sequestration of pharmaceuticals. Many chemicals used in clinical settings and beyond are associated with serious side effects requiring careful formulation to enhance their therapeutic efficacy. The goal of the proposed research is to employ methods of computational and experimental chemistry to develop novel, cavity-containing molecules and examine their capacity for trapping therapeutically important compounds in aqueous media. By elucidating the mechanisms of such selective entrapment, the research will establish a foundation for improving therapeutic action and minimizing toxic effects through targeted delivery or sequestration. In this way, the program will stimulate economic growth in biotechnology, impact the bioeconomy, and improve public health. Undergraduate and graduate students will be engaged with novel ideas, cutting-edge research, scholarly discussions, and collaboration with industrial partners. The first objective of the program is to create polyanionic, and polydendritic pS or pR pillar[6]arenes with nonpolar binding pocket buried within multiple anionic groups. Such novel hosts, with stable pS or pR planar chirality, will then be probed for including chiral steroids possessing rigid framework, variable charges, and different number of stereogenic centers. Structure-activity relationships will provide knowledge that facilitates the development of accessible pillar[6]arenes capable of stereoselective complexation of pharmaceuticals in water. The second objective of the program centers on developing polyanionic dendritic baskets, comprising ultra-deep and narrow aromatic pocket complementary to alkaloids. A series of binding studies, will provide basic understanding about effective and selective inclusion complexation of these alkaloids for their facile detection, isolation, and sequestration. With computational studies showing delta-cyclodextrins encircling the bottom portion of molecular baskets, the third objective of the program is to examine the formation of the cyclodextrin encircled baskets and quantify their affinity for encapsulating toxic anticancer drug methotrexate. The aim is to develop ways for boosting the action of baskets as sequestration agents in the allosteric fashion. 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.