Project Title: Development of amine oxide quinone methide precursors as prospective resurrecting agents for aged acetylcholinesterase
Project Mentor: Christopher Callam – Chemistry and Biochemistry
Organophosphorus (OP) nerve agents can act as a deadly chemical warfare agent through distressing the respiratory, cardiovascular, and central nervous system. This distress is caused by the inhibition of the enzyme acetylcholinesterase (AChE). AChE is an all-important enzyme that helps to control acetylcholine concentrations in the post-synaptic junctions. As AChE becomes inhibited by OP intoxication the central nervous system becomes increasingly overstimulated.
Inhibited acetylcholinesterase goes through an aging process where the phosphorylated serine residue in AChE becomes dealkylated. At this stage, current treatments are ineffective. In order to resurrect AChE a realkylation event must take place leading to the ability to reactivate AChE, and no known FDA approved treatment is capable of doing this. This led to the requisite need for a novel treatment that can react with an OP-aged AChE in order to resurrect it back to its native functional form.
Our team has been able to show that phenol-based quinone methide precursors (QMPs) can act as a resurrector of OP-aged AChE. Some of the best performing molecules had an amine substitution in the 2-position of a p-cresol frame. There have been many different derivatives of this framework tested, but an extensive look at specific amine derivatives has yet to be accomplished. This presentation will look at the synthesis of a library of molecules focusing on amine oxide derivatives. Amine oxides have an interesting charge distribution that is worthwhile to investigate to further elucidate the electronic interactions between QMPs and OP-aged AChE. Amine oxides are similar to oximes which have been shown to be effective realkylating agents. These specific amine oxide derivatives were evaluated against OP-aged human AChE with the purpose of identifying a novel molecule that can resurrect aged AChE.