In memory of Dr.D ouglas Cerasoli, ab eloved colleague and friend, who worked tirelessly to improve medical countermeasures against organophosphorus chemicaln erve agentsa tt he US Army MedicalR esearch Institute of ChemicalD efense and who left his family, friends and colleagues too early in life

A new and powerful active anode system that can be operated in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) has been discovered. In HFIP the molybdenum anode forms a compact, conductive, and electroactive layer of higher-valent molybdenum species. This system can replace powerful but stoichiometrically required Mo reagents for the dehydrogenative coupling of aryls. This electrolytic reaction is more sustainable and allows the conversion of a broad scope of activated arenes.

After the inhibition of acetylcholinesterase (AChE) by organophosphorus (OP) nerve agents, a dealkylation reaction of the phosphylated serine, referred to as aging, can occur. When aged, known reactivators of OP-inhibited AChE are no longer effective. Realkylation of aged AChE may provide a route to reversing aging. We designed and synthesized a library of quinone methide precursors (QMPs) as proposed realkylators of aged AChE. Our lead compound (C8) from an in vitro screen successfully resurrected 32.7 and 20.4% of the activity of methylphosphonate-aged and isopropyl phosphate-aged electric-eel AChE, respectively, after 4 days. C8 displays properties of both resurrection (recovery from the aged to the native state) and reactivation (recovery from the inhibited to the native state). Resurrection of methylphosphonate-aged AChE by C8 was significantly pH-dependent, recovering 21% of activity at 4 mM and pH 9 after only 1 day. C8 is also effective against isopropyl phosphate-aged human AChE.

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.

Es wurdeein leistungsfähiges aktives Anodensystem entwickelt, das in 1,1,1,3,3,3-Hexafluor-2-propanol (HFIP) eingesetzt werden kann. Die Molybdänanode bildet in HFIP eine kompakte,l eitfähige und elektroaktive Schicht aus hçhervalenten Molybdänspezies.D ieses System kann als Ersatz fürl eistungsfähige,a ber stçchiometrisch notwendige Mo V -Reagenzien in dehydrierenden Kupplungen von Arenen eingesetzt werden. Diese Elektrolyse ist nachhaltiger und ermçglichtd ie Umsetzung eines breiten Spektrums von aktivierten Arenen.Schema 1. Vergleich zwischen stçchiometrischen Mo V -und elektrokatalytischendehydrierenden Kupplungen.