TOPICS IN CONFORMATIONAL ANALYSIS AND MEDICINAL CHEMISTRY: I. HFIP SOLVATION MODULATES CONFORMATIONAL AND CONFIGURATIONAL EQUILIBRIA; II. SMALL MOLECULE APPROACHES IN TARGETING RNA AND RNA BINDING PROTEINS; AND III. BACKBONE EDITING OF OXIDIZED POLYE

This dissertation explores applications of physical organic chemistry, spanning solvent effects on conformational equilibrium, targeted drug discovery, and polymer functionalization. Chapter 1 establishes HFIP as a privileged solvent for controlling conformational equilibria, demonstrating its ability to impose substantial energetic penalties (ΔG up to 1.93 kcal/mol) on axial substituents in 1,3-dioxanes and other heterocycles through specific hydrogen-bonding interactions. Chapters 2–4 focus on drug discovery. Chapter 2 reveals fundamental challenges in designing HuR-targeting PROTACs, as the protein aberrantly engages linker moieties, precluding productive ternary complex formation. Chapter 3 addresses some of these limitations through replacement of the promiscuous hydroxamic acid warhead of KH-39 with amino acids, yielding selective HuR inhibitors (e.g., 3.04b, Ki = 530 nM) that avoid off-target HDAC inhibition and mutagenicity associated with hydroxamates. Chapter 4 deciphers structure-activity relationships of TPP riboswitch binders, identifying critical electrostatic and conformational requirements. This investigation enabled development of a second generation inhibitor, 4.17 (Kd = 57 nM), and serves as a proof-of-concept for RNA-targeted drug discovery. Chapter 5 transitions to polymer chemistry, demonstrating a tandem C–H oxidation/azide-mediated rearrangement to convert polyethylene into “PE-like” materials with tunable properties (e.g., crystallinity, degradability). This backbone-editing strategy enables modular installation of functional groups (esters, amides, chirality) and highlights potential for upcycling commodity plastics.