Organophosphorus nerve agents (OPs) are a very toxic class of compounds, and
compounds for which there is a great need of effective therapeutics. OPs are phosphoryl-
containing compounds that are typically used as pesticides and have been used as
chemical warfare agents. The toxicity of OPs is derived from the inhibition of
acetylcholinesterase (AChE), an enzyme found in the human body that regulates levels of
the neurotransmitter acetylcholine. OPs inhibit AChE by undergoing nucleophilic attack
by the catalytic Ser203 residue. However, while a water molecule is sufficiently
nucleophilic to attack the carbonyl center and break the C–O bond between acetylcholine
and Ser203 in the normal catalytic cycle, a water molecule is not sufficiently nucleophilic
to attack the phosphoryl center. Addition of a stronger nucleophile, such as an oxime, is
effective for attack at the phosphoryl center and cleavage of the P–O(Ser203) bond in
order to reactivate AChE. However, a second reaction occurs in the inhibition process,
called “aging,” in which the phosphoryl O-alkyl functionality is dealkylated creating an
anionic phosphate or phosphonate in the active site. After aging has occurred, oximes are
no longer able to attack the phosphoryl center to reactivate AChE.
Since the aging process is simply dealkylation of the O-alkyl group, the logical
solution for reactivation of aged AChE would be to realkylate the OP to replace the
departed alkyl group with a new alkyl group. Therefore, an efficient alkylating agent
must be developed. One such alkylating agent, quinone methides (QMs), could possibly be utilized as they have previously been shown to have highly tunable reactivity and can
be administered in an unreactive prodrug form.
In this thesis, the relationship between structure and reactivity of quinone
methides were investigated. The reaction mechanisms for alkylation of the QMs were
modeled using computational methods. The electronics of the substituents on the ring, as
well as the leaving group at the benzylic carbon, contribute to the reaction energetics, for
both the concerted and stepwise mechanisms of the alkylation reaction. Electron-
withdrawing substituents have been demonstrated to destabilize the electron-poor QM
ring, thereby making QM formation less favorable. However, the same electron-
withdrawing substituents make alkylation of the QM intermediate more favorable due to
destabilization of the ring. The exact opposite is true of electron-donating groups, which
stabilize the QM intermediate, favoring QM formation, but disfavoring the subsequent
alkylation reaction. The leaving group at the benzylic carbon also contributes to the
reaction energetics, mainly due to the relative nucleophilicity of the departed leaving
group.
Based on our computational studies, we sought to establish an experimental
protocol for monitoring both the quinone methide intermediate and the alkylation
reaction in general by UV-vis and GC-MS techniques. Alkylation of the QM precursors
with various nucleophiles at multiple temperatures was observed by GC-MS methods,
while the QM intermediate of the di-t-butyl precursor could be monitored by time-
resolved UV-vis spectroscopy. These data demonstrate that the reactivity of the QM precursors can be greatly modulated and tuned, and thus may be ideal candidates for
realkylation of aged AChE.