Project Title: “Exploration of substituted quinone methide precursors as potential resurrectors of aged acetylcholinesterase”
Mentor: Christopher Callam – Chemistry and Biochemistry
Spring Reserach Festival Poster
Abstract
Organophosphorus (OP) nerve agents serve as deadly chemical weapons due to their ability to induce respiratory, cardiovascular, and central nervous system symptoms by inhibiting the enzyme acetylcholinesterase (AChE). AChE is a critical enzyme in the body, responsible for regulating acetylcholine concentration in post-synaptic junctions, and when deactivated by OP intoxication, results in overstimulation of the central nervous system.
Current treatments for organophosphorus poisoning are futile after a very short time-window, during which, the inhibited acetylcholinesterase undergoes an aging process where the phosphylated serine residue of AChE is dealkylated. As a result, it is no longer reactivatable via the current FDA approved treatment methods, thereby necessitating a novel treatment that can react with the OP-aged form of AChE to resurrect it back to the native form.
Previous work by our team has shown that phenol-based quinone methide precursors (QMPs) can serve as resurrectors of OP-aged AChE. One of the best performing compounds had a methyl substituent in the 4-position of the phenol ring. Although various substituents have been tested on the phenol framework, an extensive study of this position is unprecedented. This presentation will discuss the synthesis of compound libraries derivatizing the 4-position of the phenol based QMP with different electron donating and withdrawing groups. These libraries were screened against OP-aged human AChE with the intent of identifying a robust compound that can resurrect the aged AChE.
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