Alzheimer’s disease is characterized by dysregulated production of reactive oxygen species (ROS), driving oxidative stress and subsequent neuronal degeneration. Antioxidant enzymes such as superoxide dismutase (SOD) play a central role in maintaining redox homeostasis; however, their activity is compromised in individuals with Alzheimer’s disease. Although small molecules have been developed in the past to mitigate oxidative stress, their clinical translation has been limited by poor blood-brain barrier permeability and suboptimal drug-like properties. In this work, we present a multi-step synthetic strategy for a pyridine-based tetra-aza macrocycle designed to improve blood–brain barrier permeability while retaining multi-target antioxidant activity.

The shape of a drug will determine how it interacts in the body. For it to work, it must dissolve, be absorbed into the bloodstream, avoid breakdown, enter the cell and bind to its target. Each of these steps likely requires a different shape. The pharmaceutical industry has historically only focused on the shape required to bind the target. This research has identified molecules that can readily adopt multiple shapes. These ring-shaped molecules (called macrocycles) represent a new model for drug design. Usual drugs (ie ibuprofen) are small and interact with a specific target to stop a chemical reaction. Macrocycles can work by an additional mechanism. They are larger and can interfere with interactions between proteins but are still small enough to travel the body. The preparation of these macrocycles is inexpensive and quick, properties that are important for the pharmaceutical industry. This poster describes the design and synthesis of a macrocycle and an analysis of the shapes that it adopts.

Every 65 seconds, someone develops Alzheimer's disease, which is the seventh leading cause of death in the United States. A major barrier to potential therapeutics is the permeability of these molecules across the blood-brain barrier. We have developed small molecules with strong reactivity to combat the oxidative stress known to cause Alzheimer’s disease. However, the permeability is less than ideal. As a result, my goal is to produce a molecule that has enhanced permeability but retains the reactivity of the parent molecules. To achieve this, the BOILED-Egg model assessed different derivatives of our parent molecule, Py2N2. This model showed the differences in lipophilicity among different Py2N2 compounds and how they impact permeability into the blood-brain barrier and gastrointestinal tract. Background information on our parent molecule and its function regarding Alzheimer's development will be outlined to give a scope of what these compounds can target and how they function. Compounds with high lipophilicity reflected in the model will have schemes of synthetic synthesis for future directions.

Perfluoroalkyl substances (PFAS), known as "forever chemicals", are ubiquitous environmental contaminants whose remarkable persistence poses significant risks to human health and ecosystems. Thus, it is important to develop analytical assays to determine PFAS concentrations based on widely accessible, readily available instrumentation, such as UV-VIS spectrophotometry. Tetrasodium tetraphenylporphyrintetrasulfonate (TPPS) is a water-soluble porphyrin known for its spectrophotometric property in water. It is also known that TPPS binds to the protein bovine serum albumin (BSA). We investigated the effect of BSA on the absorption spectrum of TPPS and how PFAS presence impacts BSA-TPPS interaction in water. Interestingly, we found that BSA induces TPPS precipitation. As BSA concentration increases, TPPS solubility first dramatically decreases, then increases, ultimately leading to the formation of homogeneous solutions at relatively high BSA concentration. Furthermore, addition of two different PFAS, sodium perfluorohexanoate and potassium perfluorobutanesulfonate salts, to homogeneous BSA-TPPS mixtures appreciably alter TPPS spectra. Our results show that these mixtures can be used to produce calibration curves relevant to the determination of PFAS concentrations in water.

Some of the most effective drugs from Nature are large and ring-shaped, so-called macrocycles. Macrocycles are interesting because they can interfere with protein-protein interactions, a different strategy for therapy than that used by small molecules (like aspirin). The challenge with the design of macrocycle drugs is that they are difficult to make and behave unpredictably. Here, an efficient strategy to make macrocycles is described. These molecules behave consistently (with preserved shapes) and can be tailored to optimize binding (a hallmark of drug design). The two macrocycles described differ in the choice of one group with significant (and predictable) consequences. Both groups mimic amino acid sidechains that are implicated in protein-protein interactions. One amine, N-methylbenzylamine, yields a macrocycle that will adopt six conformations in solution (an advantage when looking for drugs). The second amine, isobutylamine, gives more than eight conformations. Structural analysis was accomplished by NMR spectroscopy.