Synthesis of Functionalized Self-Assembled Cage Systems, and their Application to Biomimetic Catalysis, Sensing and Molecular Recognition

Biosensing and Molecular Recognition with Shape-selective Water-soluble Receptors.

This project involves the synthesis and application of self-assembled host molecules that are capable of function. Our goalis to use a ground-up chemical synthesis approach to create enzyme-mimicking catalytic hosts. The general feature present in biomolecules, but absent in many synthetic receptors, is the presence of reactive functionality on the interior of the active site. We have synthesized a number of functionalized self-assembled metal-ligand cage complexes withinternal functions that control complex self-assembly processes, directing their sorting properties and post-assembly reactivity. We aim to create new functional synthetic receptors via metal-ligand based self-assembly, and study their applications in supramolecular biomimetic catalysis. A wide variety of catalytically active host cages can be synthesized from a simple core scaffold via controlled self-assembly, and these cages can show enzyme-mimicking reactive properties.

Selected References:

  • Ngai, C.; Sanchez-Marsetti, C. M.; Harman, W.H.; Hooley, R.J. “Supramolecular Catalysis of the oxa-Pictet-Spengler Reaction with an Endohedrally Functionalized Self-Assembled Cage Complex” Angew. Chem. Int. Ed. 2020, 59, 23505-23509.
    DOI: 10.1002/anie.202009553

  • Ngai, C.; Bogie, P.M.; Holloway, L.R.; Dietz, P.C.; Mueller, L.J.; Hooley, R.J. "Cofactor-Mediated Nucleophilic Substitution Catalyzed by a Self-Assembled Holoenzyme Mimic" J. Org. Chem 2019, 84, 12000-12008.
    DOI: 10.1021/acs.joc.9b01880

  • Bogie, P.M.; Holloway, L.R.; Ngai, C.; Miller, T.F.; Grewal, D.K.; Hooley, R.J. "A Self-Assembled Cage with Endohedral Acid Groups both Catalyzes Substitution Reactions and Controls their Molecularity"Chem-Eur. J. 2019, 25, 10232-10238.
    DOI: 10.1002/chem.201902049

  • Holloway, L. R.; Bogie, P. M.; Lyon, Y.; Ngai, C.; Miller, T. F.; Julian, R. R.; Hooley, R. J. "Tandem Reactivity of a Self-Assembled Cage Catalyst with Endohedral Acid Groups" J. Am. Chem. Soc. 2018, 140, 8078–8081.
    DOI: 10.1021/jacs.8b03984

  • Young, M. C.; Holloway, L. R.; Johnson, A. M.; Hooley, R. J. "A Supramolecular Sorting Hat: Stereocontrol in Metal-Ligand Self-Assembly by Complementary Hydrogen Bonding" Angew. Chem. Int. Ed. 2014, 53, 9832-9836.
    DOI: 10.1002/anie.20140524

In this project, we have applied synthetic receptor molecules (cavitands) as broad scope hosts and sensors in biological environments. We have synthesized a number of functionalized cavitands, which show good selectivity and strong affinity for soft cations such as choline or peptides modified with trimethyllysine. This can be employed to perform fluorescence displacement assays (FDA) of a variety of biorelevant targets, most notably post-translationally modified histone peptides. The sensors can be used to monitor the site-selective function of histone modification enzymes, such as methylases, kinases, and phosphatases, and target recognition is possible in biomimetic lipid membranes and living cells.

Selected References:

  • Gill, A.D.; Hickey, B.L.; Zhong, W.; Hooley, R.J.* “Selective Sensing of THC and Related Metabolites in Biofluids by Host:Guest Arrays” Chem. Commun 2020, 56, 4352-4355.
    DOI: 10.1021/ja401273g

  • Gill, A.D.; Hickey, B.L.; Wang, S.; Xue, M.; Zhong, W.; Hooley, R.J.* “Sensing of Citrulline Modifications in Histone Peptides by Deep Cavitand Hosts” Chem. Commun. 2019, 55, 13259–13262.
    DOI: 10.1039/C9CC07002H

  • Liu, Y.; Lee, J.; Perez, L.; Gill, A. D.; Hooley, R. J.*; Zhong, W.* “Selective Sensing of Phosphorylated Peptides and Monitoring Kinase and Phosphatase Activity with a Supramolecular Tandem Assay” J. Am. Chem. Soc. 2018, 140, 13869–13877.
    DOI: 10.1021/jacs.8b08693

  • Liu, Y.; Perez, L.; Gill, A. D.; Mettry, M.; Li, L.; Wang, Y.; Hooley, R. J.*; Zhong, W.* “Site-Selective Sensing of Histone Methylation Enzyme Activity via an Arrayed Supramolecular Tandem Assay” J. Am. Chem. Soc. 2017, 139, 10964–10967.
    DOI: 10.1021/jacs.7b05002

  • Liu, Y.; Perez, L.; Mettry, M.; Gill, A. D.; Byers, S. R.; Easley, C. J.; Bardeen, C. J.; Zhong, W.; Hooley, R. J. "Site Selective Reading of Epigenetic Markers by a Dual-Mode Synthetic Receptor Array" Chem. Sci. 2017, 8, 3960–3970.
    DOI: 10.1039/C7SC00865A


University of California, Riverside, 444 Chemical Sciences, 501 Big Springs Road, Riverside, CA 92521