Wallace, Daniel2025-01-092025-01-092025-01-09http://hdl.handle.net/10393/50063https://doi.org/10.20381/ruor-30832Transglutaminase 2 (TG2) is a multifunctional, calcium-dependent enzyme that is ubiquitously expressed in the human body, capable of both acyltransferase and G-protein activities. The activities of TG2, when dysregulated, can contribute negatively to several physiological conditions including celiac disease, fibrosis, and cancer. Despite these contributions, there are currently no marketed clinical therapies that directly target the action of TG2. To aid in the development of methods to combat the negative effects of TG2, and to better understand the enzyme as a whole, this thesis focuses on developing small molecules capable of inactivating TG2’s catalysis. Described herein are the design, synthesis, and kinetic evaluation of irreversible covalent inhibitors of TG2’s acyltransferase activity. All molecules included maintained an established acrylamide-based inhibitor scaffold with systematic variation to one end of the molecule using cycloalkyl and aromatic hydrophobic groups by a novel synthetic approach. This was done to determine if this scaffold’s inhibition efficiency could be optimized by tailoring the hydrophobic group structure to TG2’s hydrophobic “D-site.” General trends were elucidated from the kinetic results of these inhibitors regarding hydrophobic group structures that can be employed in the design of future TG2 inhibitors with this scaffold. The investigation also identified several compounds with some of the highest inhibition efficiencies of any known irreversible inhibitor of TG2: compounds 5a, 12b, and 12c. These inhibitors may be valuable tools for subsequent research of TG2 and treatments addressing the pathological conditions that involve the enzyme.enMedicinal ChemistryTransglutaminase 2Thesis