In the past two centuries, tuberculosis (TB) has killed over 2 billion people. TB is an airborne contagious infection that usually attacks the lungs and can spread to the brain and spine. Today TB is treated with 6-12 months of antibiotics and if the medication is ended early the treatment is ineffective. There are also drug resistant forms of TB that are caused by mutations of the bacteria and this process is sped up by the overprescribing of antibiotics which is a growing problem. Dr. Jeffrey Aube created a drug that attacked both non replicating and replicating TB bacteria in the body. This was a major step from previous medicines that could only attack one. We are creating a library of TB drugs that are customizable, efficiently made, and easily purified. These customizable drugs will not only create a large range of effective medicines but also can treat TB that is resistant to antibiotics. Tuberculosis is still one the leading infectious disease killer today, claiming 1.5 million lives annually and we are making drugs that could change that and save millions of lives.

Pyridinophane molecules have recently been shown to have both antioxidant and pharmacological properties suitable for therapeutic applications targeting neurodegenerative diseases, including Alzheimer’s. We have synthesized derivatives of the parent molecules with substitutions on the pyridine ring (L1) or on the ‘side’ of the macrocycle (L2) designed to increase the antioxidant activity beyond that of the parent molecule in hopes of producing a molecule suitable for pharmacological testing in animal models. The lab is currently working towards substituting on the ‘bottom’ of the macrocycle (L3) to characterize and compare substitutions at each of the three positions.

Macrocycles are molecules containing at least one ring composed of 12 or more atoms. Macrocyclic drugs have been used clinically for decades. Many interfere with protein-protein interactions. Therapeutic intervention requires that macrocycles remain flexible to facilitate the adoption of different conformations. Specifically, small compact hydrophobic conformations are required to cross cell membranes. The ability of a macrocycle to perform these contortions is predicted by its octonal:water partition coefficient, its so-called logP. Macrocycles (as well as small molecule drugs) that are suitable for oral delivery have a logP value <5. In this study, methionine containing macrocycles are studied. The studies commence with the synthesis of a macrocycle with a dimethylamine auxiliary group that allows for solution-phase NMR analysis. Upon formation of the macrocycle, oxidation to sulfone and sulfoxide derivatives was executed. These macrocycles are of interest because the impact that oxidation has on log P values has not been reported. Additionally, S-oxidation could change the conformation of the molecules. Synthesis beings with substitution of trichlorotriazine with BOC-hydrazine, followed by treatment with methionine in basic conditions. The final substitution of the triazine installs the auxiliary group, dimethylamine (NMR). Amidation with 1,1-diethoxypropyl amine using a peptide coupling reagent yields the monomer. Cyclization using TFA yields the macrocycle. NMR spectroscopy confirms macrocyclization and gives insight into the solution conformation of the molecule. Oxidation strategies and the results of logP analysis will be developed.

Proper functioning of BRCA1 and PALB2 are essential in preventing tumor formation. Upon detection of DNA damage, BRCA1 binds to PALB2, leading to formation of the BRCA1-PALB2-BRCA2 DNA repair complex which is recruited to double-stranded break sites. Mutations in the genes coding for BRCA1 and PALB2 may disrupt this binding interaction, causing obstructions in DNA damage repair and increased breast cancer risk. Variants of unknown significance (VUS) found in breast cancer patients are genetic variants whose impact on the health of individuals are not yet known. Our study characterizes the effects of these VUS on the BRCA1-PALB2 binding interaction. Site-directed mutagenesis was used to generate BRCA1 and PALB2 VUS. It was found that the binding event between BRCA1 and PALB2 is enthalpic in nature and can be measured adequately via isothermal titration calorimetry (ITC). Thus, ITC was employed to identify whether the VUS disrupted binding. ITC data suggest that several PALB2 and BRCA1 VUS exhibit disruptions of the BRCA1-PALB2 binding interaction, but to varying degrees. We will share the data for variants tested thus far and emerging themes for prediction of the roles residues in both proteins play in the vital interaction.

Alzheimer’s Disease (AD) affects over 6.5 million Americans over the age of 65. Previous research links AD with the aggregation of Amyloid-beta-40 (AB40) in the brain, which creates neurotoxic plaques, causing further development of AD in the brain. A potential therapeutic mechanism in the treatment of AD is using drugs that will prevent the formation of these plaques, which is possible with Metal Chelation Therapy.
Metal ion chelation ideally stops metal ions from aiding in the aggregation of AB40. However, to deliver metal chelating agents to the brain, a drug-delivery mechanism is required that will be able to deliver this medicine across the Blood-Brain Barrier. Porous silica is a potential drug delivery material due to its particle size, high loading capacity, tunability, and biocompatibility. Along with these characteristics, porous silica can create a “sustained” release of a given drug, allowing for a slow and steady release profile, reducing the risks of medication side effects.
This project seeks to establish the optimal loading capacities of a class of potential AD therapeutic molecules known as pyclens into porous silica, each with different pyridyl moieties and chemical functionalities along the rim of the molecule. Encapsulation efficiencies measurements for these pyclen derivatives reveal loading percentages in the 10-19% range, varying by pyclen identity. Additionally, release studies monitored diffusion over time to find which pyclen molecule achieved “sustained” release. All loaded pyclen species were able to show sustained release after 20 minutes. Additional release studies of these molecules in the presence of copper (Cu2+) remain to be completed to ascertain the ability of release drugs in the presence of Cu2+ to inhibit AB40 aggregation, followed by independent assays of AB40 solubility under such conditions.