Synthesis of Fluorobenzyl Alkylators: Studies Toward Realkylation of Aged Acetylcholinesterase
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Date
2016-05
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The Ohio State University
Abstract
Acetylcholinesterase (AChE) is an enzyme found in the central nervous system that is responsible for hydrolyzing acetylcholine into choline and acetic acid. Organophosphorus compounds (OPs) like tabun and sarin are used as pesticides and chemical warfare agents. These OPs covalently bond to the oxygen in the Serine-203 residue in the active site of AChE resulting in inhibition of the enzyme. There are known therapeutics, pyridinium oximes, that can reverse this inhibition and reactivate the AChE if administered within the aging time frame. If left untreated, AChE complex will undergo an irreversible process where the oxygen attached to the phosphorus loses its alkyl group. This highly stable inhibited enzyme is said to be “aged,” and does not respond to the pyridinium oximes. There are currently no pharmaceuticals to reverse this aging process. Without functioning AChE, acetylcholine builds up and can lead to serious adverse health effects such as vomiting, paralysis, and eventual death by respiratory failure. The aging process can vary from minutes to hours depending on the toxicity of the specific OP. Our research focuses on synthesizing a small organic compound that can re-alkylate the aged enzyme. Quinone methide precursors (QMPs) are of interest because they are similar to other molecules that bind to the active site of AChE. QMPs have previously been shown to act as electrophiles for alkylations in biological systems. The use of computational modeling has helped us design the QMPs to be synthesized. The synthesis and initial kinetic testing of electron withdrawing re-alkylators will be discussed.
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Keywords
Acetylcholinesterase, Fluorobenzyl compounds, Alkylators, Synthesis