The Preparation of Quinone Methide Precursors to Resurrect Aged Acetylcholinesterase
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Date
2019-05
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The Ohio State University
Abstract
Organophosphorus (OP) compounds are known to have detrimental effects on the enzyme acetylcholinesterase (AChE). AChE is found in the central and peripheral nervous systems. This enzyme hydrolyzes the neurotransmitter acetylcholine (ACh) into choline and acetate. When AChE is exposed to OP compounds, such as pesticides or chemical nerve agents, AChE is covalently inhibited and after a period of time, goes through an aging process. When the enzyme is inhibited or aged, this leads to a buildup of acetylcholine in the body. In this state, the side effects include muscle twitches, reduced vision, paralysis, vomiting, convulsions, and eventually death. A group of compounds known as pyridinium oximes can reactivate the inhibited AChE. However, when the enzyme becomes de-alkylated and is aged, there are currently no known pharmaceutical treatments for this state. Our research focuses on developing small molecules that can be used to re-alkylate and subsequently resurrect the aged enzyme. Computational studies and literature show that compounds known as quinone methides (QMs) and quinone methide precursors (QMPs) have the ability to act as a re-alkylating agent. Our research involves synthesizing a family of QMP compounds that can be used to resurrect aged AChE. Our current library of compounds consists of substituted aryl frameworks such as benzene and pyridine with a variety of functional groups. Changing these groups allows us to analyze both electronic and steric interactions that allow for them to be potential re-alkylators and resurrectors. This thesis will discuss multiple synthetic schemes of QMPs in effort to realkylate and resurrect aged AChE and the biochemical screening of these compounds.
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Keywords
Chemistry, Acetylcholinesterase, QMPs, Acetylcholine, Synthesis