Date of Award
Department or Program
Glenn C. Micalizio, Ph.D.
Fatty acids interact with a wide variety of proteins, as they are either directly or indirectly involved in essentially every physiological process. Mimetics of these fatty acids have the potential to address unique issues associated with these proteins, in ways that the native ligands cannot. The pharmacological panel of targets for fatty acid mimetics is very large and comprises nuclear hormone receptors, cell surface receptors, and enzymes. This thesis describes approaches to the design and synthesis of novel fatty acid mimetics. Specifically, techniques introducing chirality and conformational constraints are employed to produce potent and selective modulators of various receptors. Synthetically, these efforts were made possible using titanium-mediated cross-coupling technology. The targeted receptors described within this dissertation include an AraC transcription factor, ToxT, two cell surface receptors, GPR40, and GPR120, as well as a nuclear hormone receptor, TLX. Its contents include a novel class of fatty acid mimetic inhibitors for ToxT, including the most potent inhibitor of the circulating strain affecting this receptor ever described. This panel is based on a chiral hydrindane, and the bound conformation of the native ligand was exploited for their design and synthesis. Also included is a collection of acyclic mimetics of oleic acid, which were used to conformationally profile this fatty acid at GPR40, GPR120, and TLX – a novel approach which does not rely on having iii detailed structural information that reveals how the conformationally labile endogenous fatty acid ligand binds to the receptor of interest. As the knowledge of our physiology as well as the roles of nutritional and endogenously formed fatty acids grows, the number of fatty acid targets is expected to expand. Thus, fatty acid mimetics are expected to continue to gain relevance and hold huge pharmacological potential.
Markham, Lauren Elizabeth Ph.D., "Design and Synthesis of Chiral, Conformationally Constrained Fatty Acid Mimetics" (2023). Dartmouth College Ph.D Dissertations. 157.