Study of para-Quinone Methide Precursors toward the Realkylation of Aged Acetylcholinesterase
| Autor: | Tyler Secor, Travis G. Blanton, Ryan J. Yoder, Craig A. McElroy, Carolyn S. Reid, Sydney B. Sillart, Christopher S. Callam, Christopher M. Hadad, Qinggeng Zhuang, Jason D. Brown, Jeremy M. Beck, Leah Guerra, Andrew J. Franjesevic, Özlem Doğan Ekici |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
chemistry.chemical_classification
biology 010405 organic chemistry Stereochemistry Organic Chemistry Active site 010402 general chemistry 01 natural sciences Biochemistry Quinone methide Acetylcholinesterase Phosphonate 0104 chemical sciences Quinone chemistry.chemical_compound Enzyme chemistry Drug Discovery medicine biology.protein Acetylcholine Nerve agent medicine.drug |
| Zdroj: | ACS Medicinal Chemistry Letters. 8:622-627 |
| ISSN: | 1948-5875 |
| DOI: | 10.1021/acsmedchemlett.7b00037 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
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