Quinone Methide Precursors as Resurrectors of Aged Acetylcholinesterase: A Synthetic Study of Quinone Methide Precursors
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Date
2019-05
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The Ohio State University
Abstract
In 2013, and again four years later, sarin gas was employed in a chemical attack against civilians in Syria; in 2017, VX in the assassination of Kim Jong-nam, the half-brother of Kim Jung-un; in 2018, Novichok in the attempted assassination of Sergei Skripal and his daughter. Sarin, VX, and Novichok, as well as a host of other compounds, are classified under a family of nerve agents known as organophosphorus (OP) compounds. These recent usages of the OPs in chemical warfare, as well as the longstanding concerns regarding the toxicity of OP-based pesticides, have brought these compounds into the limelight. The toxicity of OP compounds is founded in their ability to inhibit acetylcholinesterase (AChE), the enzyme involved in the hydrolysis of a key neurotransmitter involved in muscarinic and nicotinic activity, acetylcholine (ACh). When exposed to an OP molecule, AChE binds to the nerve agent by nucleophilic attack via the serine 203 residue at the active site of the enzyme. This enzymatic inhibition leads to an accumulation of ACh at muscarinic and nicotinic receptors, which can be fatal without treatment. Standard decades-old treatments involving atropine and oximes that are presently employed are capable of treating OP-inhibited AChE to a limited extent. However, given time, OP-inhibited AChE is dealkylated in a process referred to as aging; no known drugs are capable of reviving or treating aged AChE. These facts present the urgent need to develop a therapeutic agent or combination thereof that is capable of re-alkylating aged AChE and more effectively reactivating inhibited AChE.
Our research has focused on the synthesis and testing of small organic compounds that are effective in the realkylation of OP-aged AChE. In recent years, our research team has established a set of quinone methide precursor (QMP) compounds that have demonstrated unprecedented efficacy in resurrecting aged AChE—that is, converting aged AChE to its native state. QMPs were chosen for their structural resemblance to molecules that bind to the AChE active site, as well as their well-documented ability to alkylate biologically significant molecules (e.g. proteins and DNA). Various libraries of QMPs were synthesized for the purpose of more effectively realkylating and subsequently resurrecting aged AChE. Additionally, our work has further indicated that pH has an effect on performance: greater percentages of AChE activity were recovered in more basic conditions. Due to fluorine’s well-documented capabilities of favorably affecting pKa, intrinsic potency, and permeability of pharmaceutical agents, a particular emphasis on fluorinated QMPs will be presented in this project. I will present various efforts towards the synthesis and screening via OP-aged AChE assays of these QMP libraries.
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Keywords
Organophosphorus Poisoning, Chemical Synthesis, Acetylcholinesterase, Quinone Methide Precursors