Date of Award
5-11-2025
Date Published
June 2025
Degree Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Chemistry
Advisor(s)
John Chisholm
Subject Categories
Chemistry | Physical Sciences and Mathematics
Abstract
Oxoammonium salts have commonly been used to oxidize alcohols to aldehydes and ketones. More recently these reagents have been employed in several different oxidative transformations. Utilizing these reagents a new tandem elimination-oxidation process of tertiary alcohols has been developed. The new process yields an allylic ether which can be transformed to the alcohol easily through a reduction with zinc metal, removing the tetramethylpipyridyl protecting group derived form the oxoammonium salt. Mechanistically the reaction likely proceeds through oxoammonium salt mediated elimination followed by allylic oxidation through an ene-type mechanism. Due to the alcohol being protected by the easily removed oxoammonium salt, the reaction has a high atom economy. The PI3K pathway is a major cell signaling pathway that influences many important cellular functions including apoptosis. A number of enzymes participate in the PI3K pathway, facilitating the movement of signals from outside the cell membrane to the nucleus. SHIP1 is an inositol phosphatase that is one of the first enzymes that mediates responses after signals have moved across the cell membrane. Increasing SHIP1 activity has been shown to promote phagolysosomal degradation of lipids by microglia, suggesting that targeting the enzyme might have beneficial effects in Alzheimer’s disease. A bis-sulfonamide has been recently discovered that increases activity of SHIP1. Similar SHIP1 activators have been synthesized with modifications at four different key sites on the molecule have led to the creation of a number of analogues. These molecules were then tested to determine structure-activity relationships and to increase compound stability in vivo. The peptide hormone known as ghrelin is the only known hormone that stimulates hunger in humans. Ghrelin signaling has also been implicated in some disorders related to substance abuse, including alcohol use disorder and alcohol-associated liver disease. Ghrelin needs to be acylated by an enzyme called ghrelin O-acyltransferase (GOAT) in order to be recognized by its receptor and exert its effects. Inhibition of GOAT prevents ghrelin from being activated, which may have downstream effects on many different biological functions pertaining to obesity, diabetes and substance abuse. Amino phosphonate inhibitors were synthesized and tested for their ability to inhibit GOAT. Attempts were also made to use these inhibitors to identify the active site of GOAT, as it is still unknown, through labeling with a covalent inhibitor.
Access
Open Access
Recommended Citation
Anderson, Robert Eric, "Development of New Oxidative Methods and Synthesis of Small Molecules for Modulation of Biological Systems" (2025). Dissertations - ALL. 2109.
https://surface.syr.edu/etd/2109
