Date of Award
2022
Degree Type
Dissertation
Degree Name
Doctor of Philosophy in Chemistry
Specialization
Organic Chemistry
Department
Chemistry
First Advisor
Brenton DeBoef
Abstract
When I first started my graduate journey at The University of Rhode Island, I knew I wanted to pursue my research in an organic chemistry research group. I was drawn to the DeBoef Group, as their research was profoundly interesting in the sense where the group conducted research in various fields. Where each group had a name amongst the graduate students, such as “the nanopore group”, or “the polymer group”, the DeBoef Group was just what it truly is at heart, “the synthesis group”. I always wanted to be a synthetic chemist, I enjoyed the work, and taking something from pen and paper and producing a tangible product in the lab. I always thought the field of synthetic chemistry was quite beautiful in that sense. But, I guess at heart… I’m a synthetic chemist, which is why there was never any other option than to join the DeBoef Group.
At the time when I joined, in 2017, the research being conducted was dividied into two subgroups: C-H activation, including inventing new reaction methodology, and supramolecular chemistry work involving binding studies for mainly biosensing purposes. However, as the years went by, these subgroups became quite diverse in their applications and synthetic approaches. As an undergraduate, I had done some undergraduate research work involving C-H activation, so there was a sense of familiarity within the group. However, I was drawn to the more unknown facet, which was the supramolecular chemistry, or host-guest interaction, side.
I started my Ph.D. work on a C-H activation project, in which the premise involved utilizing electron withdrawing nitrogen groups, versus commonly used electron donating nitrogen groups, to catalytically induce an intramolecular transformation to form nitrogen-containing heterocycles, something of substantial interest to the field of pharmaceuticals.
My first year I did get some promising preliminary data, and presented my work at the American Chemical Society Regional Meeting in Boston in 2018, at the end of my first summer. However, after many arduous hours, we concluded that the idea wasn’t as plausible as we had hoped – something I found to be quite common in the field of synthetic research specifically. I continued to work on the project for a short time after that and later deciding to switch to the “other side” of the DeBoef Group, the side I was initially drawn to – supramolecular host-guest chemistry.
I started this research by helping a co-worker in the group, Ashvin I. Fernando, who later became a great friend and mentor to work with. I owe a lot of my advanced skills to his expertise in the supramolecular field. I started this research by working on synthesizing pillar[n]arenes, specifically pillar[5]arenes, (P5As), which are known macrocycles consisting of repeating benzene units linked by methylene bridges. P5A which are host-like molecules typically possess a hydrophobic inner cavity, perfect for binding hydrophobic moieties, including hydrophobic small molecules or hydrophobic gases, such as 129-Xenon, which will be mentioned frequently. My role with P5A was to synthesize it in large quantities and further functionalize their carbon chains, or carbon linkers, with various terminal end groups, both symmetrically and asymmetrically. This opportunity gave me a completely new view on synthetic chemistry. I am very grateful for having worked with Ashvin on his various P5A projects to learn, not only a new way of synthetically thinking, but to learn different, more complex, purification skills and syntheses setups.
This research led me to gravitate towards a different group of macrocycles, primarily cyclodextrins, (CDs), which are quite well-known and prevalent in many fields outside of just chemistry. The reason I was drawn to CDs specifically was because they were known to possess a unique hydrophilic/hydrophobic duality. Meaning, while still being able to bind a hydrophobic guest, they still, in most cases, maintained water solubility due to the exterior alcohol groups encompassing this molecule. Which for biological purposes, such as drug delivery - what I was interested in exploring and was something our group had not yet done yet, was ideal. In this dissertation, the reader will explore some interesting findings regarding cyclodextrin binding in Chapter one and Chapter two.
Chapter one focuses on the development of [2] and [3] CD-based rotaxanes, with an interesting twist towards the end, involving what we coined as a quasi[3]rotaxane – seemingly a [3]rotaxane but not quite as the complex is not fully kinetically locked in place. In this chapter, my personal favorite, the reader will learn about the synthesis of the rotaxanes, how important the chosen guest was to the work, the robustness of the rotaxanes, how we developed higher order ternary complexes using a small hydrophobic drug-mimic to demonstrate proof of concept – that it is, in fact, possible to generate a ternary complex for drug delivery, and how we can apply this system to a real life setting.
Chapter two focuses on fundamental findings regarding CD-based pseudorotaxanes, and focuses on their binding abilities by alternating between various guests. In this chapter, the exploration of the non-covalent driving focuses are discussed. Additionally, this chapter confirms some of the hypotheses presented in chapter one to demonstrate what is occurring, and lastly, how this system could potentially be used for drug delivery.
In chapter three, another macrocycle is introduced that was explored in our group before, cucurbit[n]urils, (CBs), specifically cucurbit[6]uril, (CB6). This macrocycle is different in structure, yet similar, to the previously mentioned macrocycles, in the sense that is it composed of glycouril subunits instead of glucose subunits (like CDs), but also has a hydrophobic cavity ideal for binding hydrophobic molecules, importantly 129Xe gas – a known hydrophobic gas. This is significant because it can produce a HyperCEST signal, in which CEST stands for Chemical Exchange Saturation Transfer. Simply put, this is an eloquent way of signal amplification coupled with Xenon-based MRI, a relatively new form of MRI that is much more advantageous to regularly used proton MRI.
As the reader will explore in Chapter three, we propose a new and innovative way to combine a CB6-based biosensor with this molecular imaging platform as a way of detecting early symptoms of lung cancer. The reader will learn more about HyperCEST 129Xe MRI, and why it is so advantageous over proton MRI. Additionally, this chapter will primarily focus on the synthesis of the molecular imaging biosensor, the CB6-based cleavable rotaxane. Lastly, this chapter will conclude with how this should work in a true environment to ultimately contribute to less late detected lung cancer cases.
Drug delivery and Xenon binding are both common themes that drove the ideas and syntheses discussed throughout, that the reader will see trends of the research conducted herein. It is important to note that the HyperCEST 129-Xenon MRI studies, in all cases, were done in collaboration with several individuals, listed as authors in chapter three, at the Department of Chemistry at Lakehead University and Thunder Bay Regional Research Institute, both in Thunder Bay, Ontario, Canada.
Ultimately, I want to conclude this by stating the primary role of the DeBoef Group, has been and always will be, the synthesis. We are “the synthesis group” through and through. Whether it be new reaction development, creating macrocycles, or creating guest species for binding, we will always focus on the synthesis, and taking our ideas off the paper, (to be honest, off the office windows), and applying them experimentally in the lab. Additionally, I’d like to state that all the synthetic work was done at the University of Rhode Island Department of Chemistry in conjunction with the Teknor Apex instrumentation laboratory.
Recommended Citation
Seveney, Lauren Elizabeth, "THE SYNTHETIC DEVELOPMENT OF INNOVATIVE SUPRAMOLECULAR ARCHITECTURES FOR THE PURPOSES OF DRUG DELIVERY AND BIOSENSING" (2022). Open Access Dissertations. Paper 1463.
https://digitalcommons.uri.edu/oa_diss/1463
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