To fight disease, pharmaceutical companies have historically prepared small molecules designed to interfere with specific sites on proteins (enzymes) to prevent chemical reactions from taking place. However, a second paradigm for interfering with proteins has gone largely unexplored--blocking protein-protein interactions. To accomplish the latter, large molecules are needed to bind to large areas on the protein target. However, large molecules present additional challenges. Typically, they are hard to synthesize, not orally available, and typically cannot cross cell membranes. Nature has designed large molecules like cyclosporin that should not work as drugs based on our current understanding. Despite its size, cyclosporin is orally available and can cross cell membranes. This research explores the design, synthesis, and conformational analysis of similar large ring-shaped molecules, so-called macrocycles. In this work, we are increasing the size of the ring-shaped molecule. By increasing the size of the ring-shaped molecule and varying the amino acid (in this case, valine), we are expanding the possible ways in which our macrocycle may interfere with protein-protein interactions. Here, a 26-atom macrocycle is reported. 1H NMR spectroscopy reveals a protonated molecule that is highly dynamic which has access to a beta-sheet conformation.

Macrocyclic drugs adopt multiple conformations--a behavior referred to as chameleonicity--to navigate hydrophobic cellular membranes and aqueous intracellular environments. The rules for understanding this behavior are beginning to emerge through studying existing drugs and the synthesis of model systems. Historically, one challenge to macrocycle synthesis is low yield reactions. To this end, dynamic covalent chemistry has been explored. Here, macrocycles are afforded readily by dimerization with the formation of two hydrazones.

The efficiency of the macrocyclization reaction led to the hypothesis that upon formation of the first hydrazone, the acyclic intermediate was preorganized to place the hydrazine and acetal in close proximity thereby reducing the likelihood of oligomeric or polymeric products. The preorganization could result from a network of hydrogen bonds. Moreover, in an acidic environment, wherein the triazine ring is protonated, the opportunity for bifurcated hydrogen bonds emerge. Computation has been used to identify sites for protonation and the energetic contributions of hydrogen bonding.

To explore templating and the role of protonation in the formation of hydrogen bonds, model systems were prepared that emulate ‘half’ of the macrocycle. The acetylated aminoacetal offers a well-resolved NMR spectrum. In contrast, hindered rotation about the triazine-N bond leads to a mixture of rotamers in the hydrazine component. However, upon condensation, a single rotamer is observed and resonances corresponding to the hydrogen bonded protons emerge downfield between 7-12 ppm. Computation provides estimates of the energetic contribution of the bifurcated hydrogen bond as well as the hydrogen bond formed in the absence of protonation. The results of titration and variable temperature NMR experiments will also be described.

The mis-regulation of reactive oxygen species and transition metal ions contributes to the onset of Alzheimer’s Disease. Reactive oxygen species are a natural byproduct of metal redox cycling that occurs within the body and are important in processes like homeostasis and various pathways of cell signaling. Two series of pyridinophane ligands were produced and evaluated for the ability to target the molecular features of Alzheimer’s Disease. The functionalized pyridinophanes were chosen to analyze their blood-brain barrier permeability and radical scavenging ability when included within a molecular scaffold. Preliminary results with the DPPH assay indicated a significant increase in radical scavenging activity for ligands containing electron-donating substitutions in comparison to the parent ligands. These results warrant further exploration into the mechanism of the activity observed.

Petroleum crude oil, unconventional crudes, and renewable bio-crudes are essential materials in our everyday lives. They fuel vehicles, heat buildings, provide electricity, and are used to produce a multitude of other materials, such as plastics and solvents. Crudes are highly complex chemical mixtures, estimated to contain between 100,000 and 100,000,000,000,000,000 unique molecules. Since 2015, single-molecule imaging has visualized hundreds of chemical structures, and historical literature has published thousands of proposed structures. This project builds an open database populated with published crude structures enabling data-driven analysis of these structures, and detailed workflows, allowing for easy future insertion of new molecules into the database. This database can be used to make calculations and predict characteristics of molecules, such as viscosity, density, and reactivity, which are all critical in refinery plants, transportation, and usage of these fuels. Performing queries on the molecules in the database to filter for specific characteristics allows scientists to develop more successful experiments by refining their hypotheses to account for the query results displaying possibilities of their desired outcome.  

This research aims to understand how to design and control molecular hinges. The molecular hinges of interest are nano-sized equivalents of door hinges. Such hinges could find applications in new materials or the design of new drugs.

The foundation for this research was the observation that a large, ring-shaped molecule - a so-called macrocycle – prepared by a colleague folded and unfolded rapidly at room temperature. Two research questions arose from this observation: was the hinge behavior unique to this molecule, and could the hinging rate be controlled?

Addressing these questions required the three-step synthesis of a related macrocycle. This new molecule had groups equivalent to putting grit around the hinge's pin. The difference in the rate of hinging motion due to the addition of these groups was observed using a technique called variable temperature NMR spectroscopy.

The results of this work revealed that hinging is a general phenomenon for some of these macrocycles. Second, the 'molecular dirt' designed into this new hinge reduced the rate of hinge motion from 2000 times per second to 20 times per second.

This work is being written up for communication to the Journal of the American Chemical Society based on the novelty of this molecular device and the scientific community's interest in molecular machines.