Structurally diverse functionalized hosts for the binding of cationic drugs and metabolites
Date
2023-04-27
Authors
Warmerdam, Zoey
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Abstract
The goal for my thesis is to learn about structure-activity relationships between sulfonatocalix[4]arene host and small molecule targets, to extend on the fundamental knowledge that is present in today’s literature. This was achieved using diverse synthetic approaches and supramolecular binding studies.
Chapter 1 introduces the diversity-oriented functionalization of host molecules. The topics of supramolecular chemistry, molecular recognition and diversity-oriented synthesis are introduced, and it also reviews literature on diversity-based covalent functionalization of hosts. Extra attention is spent on the calix[n]arene hosts as they form the basis for this thesis. In Chapter 2, my work on regioselective modifications of the calix[4]arene upper rim is presented. This work is fundamental going forward in my thesis, as in this chapter I establish the synthetic firsts steps of the hosts that are used throughout. I then studied the binding of nicotine and analogues by a small library of modified hosts through indicator displacement assays and NMR, to learn lessons about binding strength and geometry. I conclude that calix[4]arenes show different patterns of binding strength, geometry and selectivity depending on the upper-rim substitutions. In Chapter 3 this approach was extended to study methylated arginines and lysines and to include a wider variety of host structures. This chapter is part of a collaboration in which our collaborators contributed non-calixarene hosts with different shapes, allowing us to explain selectivity patterns by a common framework that considers the geometry, depth of binding pockets, and functional group participation across different host classes. For this I utilized indicator displacement assays and visualized our findings with molecular modelling of the complexes. I found that a more enclosed geometry of the host with a bigger binding pocket allowed for stronger interactions.
In Chapter 4 I establish a method using phage displayed peptides to synthesize a large library of calix[4]arenes with more enclosed binding pockets. The general design was to make calixarenes that are strapped by peptidic elements, I used phage-displayed peptides to bring diversity to the host library. I establish the creation of calixarene-peptide hybrids on the surface of phage and made first efforts to use an affinity pull-down to select a host from this library. A set of hosts selected through the affinity pull-down were re-synthesized and their binding constants for targeted guests were determined via indicator displacement assays. I found that the affinity pull-down did not result in strong binding host and that improvements are needed. To get a better understanding of why the hosts form weak complexes, I studied one of the complexes with 1D and 2D NMR and learned that the peptide undergoes a hydrophobic collapse creating a competition for the target of interest.
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Keywords
Supramolecular Chemistry, Host-guest Chemistry, Diversity-based covalent functionalization of hosts, Calix[4]arene