Synthesis of Quinone Methide Precursors and Derivatives to Resurrect Aged Acetylcholinesterase
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Date
2018-05
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Publisher
The Ohio State University
Abstract
Organophosphorus compounds (OPs) such as tabun, sarin and soman have been used as chemical warfare nerve agents. The advancements of chemical warfare agents used for military tactics exceed the research to reverse the toxic effects of the nerve agents. The demand to study OP nerve agents is crucial because of the damaging effects to people, the commercial availability, terrorist usage, and even the stockpiles in various countries. OP pesticides are also of significant concern as the largest number of deaths occurs due to exposure to such pesticides, especially in the third world. Exposure to OPs affects the central nervous system and causes a buildup of acetylcholine in the body by inhibiting acetylcholinesterase (AChE). The AChE is initially inhibited, followed by an aging process. There are known therapeutic oximes for reactivating the inhibited form of AChE; however, there are no known treatments for aged AChE. We are developing a library of quinone methide precursors (QMPs) to be used as potential re-alkylators in order to reverse the aging of AChE. These QMPs can be used to potentially re-alkylate the aged OP-AChE complex, followed by a subsequent reactivation step. This research is vital to enhance the pharmaceutical measures and further inspire more research done to counteract the aging process. Several frameworks were synthesized through synthetic routes including nucleophilic substitution, reductive amination, and Mannich reactions. We will present the synthesis of a small library of pyridine QMP frameworks and the screening of these compounds as re-alkylators and re-activators of both the inhibited and aged AChE (electric eel and human).
Description
Undergraduate summer research fellowship
Keywords
Nerve agents, Pesticides, Organophosphorus Compounds, reactivation, Aged acetylcholinesterase, realkylation