Date of Award

Summer 2022

Project Type

Dissertation

Program or Major

Chemistry

Degree Name

Doctor of Philosophy

First Advisor

Arthur Greenberg

Second Advisor

Christopher F Bauer

Third Advisor

Patricia M Stone

Abstract

Two model oxepins were synthesized in an attempt to model the metabolism of benzene in the human liver. 4,5-Benzoxepin was subjected to similar enzyme reactions that the oxepin metabolite itself would encounter if one was exposed to benzene. In addition, a synthesis of 2,3-benzoxepin was completed in order to compare enzyme and non-enzyme catalyzed reactions with that of 4,5-benzoxepin. In an attempt to test the validity of the enzyme reactions, the model oxepins were also reacted with a two single electron oxidizing inorganic salt, cerium (IV) ammonium nitrate (CAN) to see if the intermediates following the enzyme reaction were consistent. Other chemists in the past have postulated that oxepin undergoes further epoxidation in metabolism instead of two single electron oxidations, so a test with dimethyldioxirane (DMDO) was also performed on the model oxepins to observe if their products closer matched the enzyme reactions. Research suggests that oxepin can follow both the two single electron oxidation and further epoxidation metabolic pathways when exposed to enzymes CYP1A2 and CYP3A4 under multiple concentrations of enzyme with a fixed concentration of model oxepin substrate. Amides and lactams are common structural motifs found in a variety of natural products and construct the backbone of amino acid chains, proteins, and enzymes. Amides have 3 major resonance contributors. 4-Silatranones have been calculated previously to have the nitrogen lone pair delocalized like in normal amides vs. having a coordinate covalent bond with silicon as in silatranes, which is a bridged bicyclic amine dependent upon conformation. This research aims to synthesize strained lactams known as 4-silatranones and to help elucidate who wins the competition for nitrogen’s lone pair-the silicon via dative bond or delocalization into the amide carbonyl. Iron chelators have many biological applications including the treatment of iron overload disease, the suppression or promotion of reactive oxygen species production and even the ability to sense the iron status in the cell. Development of a chelator that can modulate and sense intracellular iron is the goal of this research. 8-hydroxyquinoline has been shown as a powerful chelating agent for iron in the past when three equivalents of 8-hydroxyquinoline have been tethered to a tripodal linker allowing for a hexadentate chelator to completely sequester iron. This portion of the project focuses on the synthesis of a tripodal linker with a carboxylic acid handle (Figure 4) to attach the chelator to lysine residue of a SS-peptide (synthesized by a research group member) that targets the mitochondria of a cell which contain labile iron pools.

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