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Topic

Deriving function from complex linked equilibria: systems chemistry with self-assembled p-sulfonatocalix[n]arenes in aqueous solution

Department of Chemistry

Date & location

• Tuesday, April 22, 2025
• 8:30 A.M.
• Elliott Building, Room 230

Examining Committee

Supervisory Committee

• Dr. Fraser Hof, Department of Chemistry, University of Victoria (Supervisor)
• Dr. Cornelia Bohne, Department of Chemistry, UVic (Member)
• Dr. Raad Nashmi, Department of Biology, UVic (Outside Member)

External Examiner

• Dr. Nathalie Katsonis, Faculty of Science and Engineering, University of Groningen

Chair of Oral Examination

• Dr. Kathy Gaul, School of Exercise Science, Physical and Health Education, UVic

Abstract

Building systems of increasing complexity can give rise to emergent properties that are otherwise unobtainable. The design and development of macrocyclic-based systems that function in aqueous solution has many applications in detection, delivery and reversal of biologically relevant molecules. This dissertation focuses on synthetic analogs of the macrocyclic host p-sulfonatocalix[n]arene, as key building blocks in the creation of self-assembled complex systems, covering applications in therapeutic design and differential sensing in aqueous solution. Chapter 1 sets the stage for this work, introducing current synthetic and systems strategies employed in biorelevant host-based sensing.

An advanced property addressed in this dissertation is the ability to achieve pan-selectivity — binding well across a whole class of target analytes while maintaining good selectivity against other chemically similar analytes. Synthesizing a host that selectively binds a target analyte can be an inefficient and arduous task. In Chapter 2, I report on the templated synthesis of new bivalent hosts, Super-sCx4 and Super-sCx5, as pan-selective binders of neuromuscular blocking agent’s (NMBA’s). Synthesis was achieved using a bisquaternary amine NMBA template, self-assembling two highly anionic p-sulfonatocalix[n]arene building blocks for covalent linkage. These bivalent anionic hosts bind by engaging both quaternary amines present on a variety of NMBA’s, making them potential candidates for host-based NMBA drug reversal. We report low μM binding to alkyl, steroidal, curarine and benzylisoquinoline NMBA’s, with selectivity over endogenous monovalent hydrophobic amines.

Another advanced property addressed in this dissertation is the ability to produce useful sensing outputs for a variety of analytes, without programming specific molecular recognition events. Differentiation of analytes by supramolecular sensors is typically achieved through sensor arrays, relying on pattern recognition responses from a large panel of isolated sensors. The differentiation of highly similar analytes poses an ongoing challenge. In Chapter 3, I explore a new one-pot systems chemistry approach to differential sensing in biological solutions. This systems approach relies on a network of three cross-assembling DimerDye p-sulfonatocalix[n]arene sensors, containing different integrated fluorophores. This robust approach exploits complex interconnected host•host and host•analyte equilibria, producing emergent supramolecular and photophysical responses unique to each analyte. We apply this inherently information-rich systems approach to the discrimination of closely related serum albumin proteins and protein mixtures, without relying on targeted recognition elements. We show that a single adaptive sensing solution provides better analyte discrimination than an analogous sensor array.

Macrocyclic host-based sensors are often limited to detecting a single class of interacting analytes because they tend to bind molecules with similar properties. In Chapter 4, I address this challenge, reporting a mixed host system that detects analytes from many different classes, including cationic, neutral, and anionic. We show that co-assembling two different macrocyclic scaffolds, DimerDye p-sulfonatocalix[4]arenes and cucurbit[n]urils (n = 7 and 8), effectively increases the scope of analyte binding interactions and sensor outputs. This simple strategy exploits cross-reactive noncovalent host•host interactions through a synthetically integrated reporter dye. Emergent photophysical responses are produced by analyte interactions to either host. We demonstrate the advantages of mixed host co-assembled sensors in an array-based platform, differentiating a range of illicit drugs and common adulterating substances. The potential of this approach is further applied in profiling real-world multi-component illicit street drug samples.