Date of Award

August 2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Chemistry

First Advisor

Alan W Schwabacher

Committee Members

Alexander E Arnold, Nicholas R Silvaggi, Mahmun Hossain, Wilfred T Tysoe

Keywords

enduracididine, Hydrogel Solid Support, Molecular recognition, Synthesis, β-sheet mimicry

Abstract

From the hydrophobic effect, which is responsible for the organization of amphipathic molecules into cellular membranes, to the highly specific hydrogen binding patterns found in DNA base pairs that keeps our genetic material “zipped up”, non-covalent and reversible interactions are critical to properly functioning biological processes. Molecular recognition is an area of study that seeks to better understand these observed phenomena. In a general sense, association of “Host” and “Guest” molecules are based on ionic forces, hydrophobic interactions, cation-π effects, π-π stacking, conformational restriction, and many others. This dissertation will primarily focus on two projects that have an emphasis on studying molecular recognition.

The first major project details the synthesis of a molecule that mimics the hydrogen bonding array of a β-sheet. β-sheets, secondary protein structures found ubiquitously in nature, are composed of peptide strands that associate through hydrogen bonds between an amide carbonyl on one strand to an amide -NH on an adjacent strand. As peptide strands begin to fold into a β-strand it pre-organizes the hydrogen bond donors and acceptors on the other edge allowing for the β-strand to propagate into a β-sheet. While this propagation is beneficial in the efficient folding of proteins, it makes it difficult for scientists to study this phenomenon in solution apart from the other complexities that exist in protein structures. Chemists have addressed this issue by creating synthetic mimics that simulate the hydrogen bonding array found in β-sheets along only one edge, greatly simplifying the observable phenomena and allowing them to study these effects in greater detail in solution.

Based on the work of previous chemists I have developed a synthetic β-sheet mimic that can replace 3 amino acids in a peptide, has fluorescent properties, and can be incorporated by solid phase synthetic methods into peptides. Using a quinolone as a fluorescent core, I have synthesized a 3,6-diaminoquinol-4-one that has the same hydrogen bonding array. Preliminary studies appear to show association with itself in organic solvents. Additionally, I have developed synthetic schemes towards a pyrido[2,g]quinolone that would retain the same hydrogen binding array with a higher degree of conformational restriction and presumed fluorescent properties. This synthetic work will allow for future graduate students to study these hydrogen bonding interactions.

The second major project in this dissertation details the work I have done on a hydrogel solid support. This work was done to enable the development of a real-time continuously monitoring sensor for the detection and quantitation of metal ions in aqueous solution.

Specific azo dyes have long been known to show a shift in their absorbance spectrum with the addition of metal ions. When used as soluble molecules they are difficult to reuse due to their strong association to the metal ions. I have developed various hydrogel polymers with covalently attached azo dyes capable of metal ion diffusion in aqueous solutions. Optimization of these hydrogels has been achieved by variation of composition, crosslink-density, co-solvent selection and glass derivatization allowing for a robust attachment to a rigid backing. These hydrogels are optically transparent, allow for removal of the metals with acidic media, and demonstrate sufficient mechanical strength to allow them to be easily moved between analyte solutions. Two separate type of polymers have been developed to allow for either alkylation or acylation reactions to produce the covalent linkage of dye to hydrogel, each with its own advantages.

With others in my research group and in collaboration with a local Milwaukee company, we have shown the azo-dyes covalently tethered to these hydrogels retain their optical properties and can be used for the identification and quantitation of aqueous metal species when incorporated into a flow cell. They are stable to hundreds of binding and release cycles and months of use, at least.

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