Cucurbit[n]uril-Type Molecular Containers

Project Summary / Abstract. The PI is Professor at the University of Maryland College Park since 1998 where he runs a lab focusing on the design and synthesis of new cucurbit[n]uril-type molecular container compounds, determination and understanding of the fundamental molecular recognition properties toward cationic guest

compounds including drugs and toxic substances in water, and demonstration of the use of these compounds in important biomedical applications via key collaborations. The pioneering and impactful research contributions of Dr. Isaacs and his group have been documented in 189 articles in peer reviewed journals which have received

over 15500 citations and garnered Dr. Isaacs election as fellow of AAAS and the 2018 ACS Chemical Society of Washington Hillebrand Prize. Dr. Isaacs’s lab is/has trained 19 PhD, 21 postdocs, 12 MS, 41 undergrad, and 2 high school students. The vast majority pursued scientific research careers including 7 University faculty who

have launched successful independent academic research groups. The PI’s service record confirms a commitment to graduate education (Director of chemistry graduate program and UMD GAANN fellowship program), community building via leadership positions in the international supramolecular and CB[n] conference

series, scientific review for numerous journals and NSF and NIH panels, and junior faculty mentoring. The vision of the research program is based on the realization that the lingering effects / presence of biologically active substances (e.g. prescription and illicit drugs, (environmental) toxins) can lead to adverse

biological events, disease, and death. Common mitigation strategies include the pharmacodynamic medicinal chemistry approach based on small molecule inhibitors and pharmacokinetic decoy protein / antibody based sequestration approaches. CB[n]-type receptors exhibit tight aq. binding toward a variety of biologically active

compounds which renders them the prime supramolecular platform for systematic development as in vivo sequestrants. Over the next five years we will master the synthesis of complex (acyclic) CB[n] receptors and delineate their structure–binding affinity/selectivity relationships toward chemically and biologically active

compounds to advance supramolecular design principles for high affinity hosts suitable as in vivo sequestrants, (targeted) delivery agents, and components of sensing ensembles. Structural variables to be probed include the nature of glycoluril oligomer / building blocks, aromatic walls, and solubility determining groups. A key aspect of

meeting this goal is the implementation of an experimental-computational feedback loop via close interactions with our collaborators. In addition, our participation in the SAMPL computational chemistry challenges by supplying blinded (acyclic) CB[n] binding constant datasets will synergistically advance methods for aqueous

binding free energies calculations.