Study of -Quinone Methide Precursors Toward the Realkylation of Aged Acetylcholinesterase

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2017 Jun 20

PMID 28626522

Citations 3

Authors

Ryan J Yoder

Qinggeng Zhuang

Jeremy M Beck

Andrew Franjesevic

Travis G Blanton

Sydney Sillart

Tyler Secor

Leah Guerra

Jason D Brown

Carolyn Reid

Craig A McElroy

Ozlem Dogan Ekici

Christopher S Callam

Christopher M Hadad

Affiliations

Soon will be listed here.

Abstract

Acetylcholinesterase (AChE) is an essential enzyme that can be targeted by organophosphorus (OP) compounds, including nerve agents. Following exposure to OPs, AChE becomes phosphylated (inhibited) and undergoes a subsequent aging process where the OP-AChE adduct is dealkylated. The aged AChE is unable to hydrolyze acetylcholine, resulting in accumulation of the neurotransmitter in the central nervous system (CNS) and elsewhere. Current therapeutics are only capable of reactivating inhibited AChE. There are no known therapeutic agents to reverse the aging process or treat aged AChE. Quinone methides (QMs) have been shown to alkylate phosphates under physiological conditions. In this study, a small library of novel quinone methide precursors (QMPs) has been synthesized and examined as potential alkylating agents against model nucleophiles, including a model phosphonate. Computational studies have been performed to evaluate the affinity of QMPs for the aged AChE active site, and preliminary testing with electric eel AChE has been performed.

Citing Articles

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