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Faculty of Graduate Studies

Chelsea Wilson

  • BSc Hons. (University of Victoria, 2019)
Notice of the Final Oral Examination for the Degree of Doctor of Philosophy

Topic

Synthesis of functionalized water-soluble sulfo-pillar[6]arene analogs for binding pharmaceuticals

Department of Chemistry

Date & location

  • Monday, October 6, 2025
  • 1:00 P.M.
  • Elliott Building, Room 305

Examining Committee

Supervisory Committee

  • Dr. Fraser Hof, Department of Chemistry, University of Victoria (Supervisor)
  • Dr. David Leitch, Department of Chemistry, UVic (Member)
  • Dr. Alisdair Boraston, Department of Biochemistry and Microbiology, UVic (Outside Member)

External Examiner

  • Dr. Adam Urbach, Department of Chemistry, Trinity University

Chair of Oral Examination

  • Dr. Adam Murray, Department of Computer Science, UVic

Abstract

Functionalized water-soluble macrocyclic hosts are increasingly realizing their potential for use in biological applications. Almost all such efforts require synthetic modification of the parent macrocycle. Through the synthetic manipulation of a host, one can tune the non-covalent interactions, driving complexation towards stronger and more selective binding, as well as introduce new functional elements. This dissertation focuses on developing new functionalization strategies for the high-affinity host sulfo-pillar[6]arene, which has growing potential in the field of supramolecular therapeutics. At the start of this thesis there were no reports of methods to modify this host, limiting its potential. This work presents synthetic approaches that provide multiple new functionalized sulfo-pillar[6]arene analogs that vary the scaffold’s surface area, anionic charge, and fluorescence properties.

This works starts with a new synthetic protocol for synthesis of ethoxypillar[6]arene, a key synthetic intermediate for water-soluble sulfo-pillar[6]arenes. Access to this material had been limited to small quantities requiring laborious purifications. The new protocol is chromatography-free and provides large (20 – 40 g) quantities of pure ethoxypillar[6]arene in a day’s work. From this point, multi-step synthetic routes allowing for modifications to multiple regions of the macrocyclic scaffold were developed.

The first scaffold modification explored was extending the binding cavity with one and two phenyl groups. This led to the development of novel extended sulfo-pillar[6]arene analogs with increased host-guest contacts. The ability of the new hosts to bind direct oral anticoagulants (DOACs) was established, and the structure-function relationships of the closely related hosts and a subset of these drugs were determined. As one example, the addition of an extended binding arm with preservation of the same overall amount of charge resulted in a 6-fold increase in affinity (Kd = 230 nM) towards the pharmaceutical agent betrixaban. Attempts at incorporating additional extending arms identified instability of the more highly substituted scaffold, highlighting the synthetic challenges of this kind of work. This modification route also introduces a new fluorescent functionality to the host, opening the door to new supramolecular sensing applications for sulfo-pillar[6]arenes.
The second modification type was controlling the cavity charge. A multi-step synthetic pathway was developed, allowing for precise control over the number (−12, −8 or −6) and spatial distribution of charges. To do this, a regioselective oxidation provided synthetic access to two or three aromatic rings in the macrocyclic scaffold. Through a hydrodeoxygenation step these rings were defunctionalized. This led to the establishment of a new class of water-soluble host with variable charge, pseudo sulfo-pillar[6]arenes. Preliminary binding data with the guest DAPI demonstrated that altering the charge has a significant effect on binding, with two (−6) regioisomers exhibiting a ~30-fold difference in affinity, and a −6 analog having equivalent potency to a −12 species. This work shows how seemingly subtle structural changes can lead to large impacts on host properties.

Overall, this dissertation presents new synthetic methods in altering the chemical composition of sulfo-pillar[6]arenes, generating five new water-soluble synthetic hosts. It explores the new hosts high-affinity binding and selectivity for a variety of pharmaceutical agents and the dye DAPI. The creation of new synthetic compounds and functionalization strategies will help in developing better supramolecular therapeutics.

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