Doctor of Philosophy, The Ohio State University, 2022, Chemistry

Organophosphorus (OP) agents are extremely toxic compounds that have been used as pesticides and chemical warfare agents. The mechanism of action by which OP compounds operate is the inhibition of the enzyme acetylcholinesterase (AChE), resulting in a cholinergic crisis and potentially death. Current treatments are limited and must be administered immediately upon exposure to an OP compound. After an OP compound inhibits AChE, a subsequent reaction, referred to as aging, occurs after a period of time that is dependent upon the chemical structure of the OP. The OP-aged forms of AChE are recalcitrant to current FDA-approved therapeutics and therefore it is of great importance to develop an effective treatment that is capable of restoring OP-aged AChE back to its native state. The Hadad group has shown that a class of compounds called quinone methide precursors (QMPs) are capable of converting OP-aged AChE back to its native state in a process referred to as resurrection. Herein is reported the synthesis of novel QMPs to be used as small molecule therapeutics for the treatment of OP-aged AChE. Additionally, the synthesis of pentacoordinate phosphorane haptens is reported, which are used to elicit the production of catalytic antibodies that selectively target and catalyze the hydrolysis of OP compounds before they have an opportunity to inhibit AChE; that is, this is a preemptive treatment akin to a vaccine. Finally, the synthesis of various OP surrogates is reported, which are used to screen QMPs for their resurrection efficacy in vitro.

Committee: Christopher Hadad (Advisor); Christine Thomas (Committee Member); Psaras McGrier (Committee Member); Jon Parquette (Committee Member) Subjects: Chemistry

Doctor of Philosophy, The Ohio State University, 2017, Chemistry

The purpose of this dissertation is to highlight three unique approaches towards discovering a catalytic treatment towards organophosphorus (OP) poisoning. All three potential approaches focus on developing catalytic treatment methods that focus on hydrolyzing OP nerve agents before they can inhibit acetylcholinesterase (AChE). AChE is a serine hydrolase which is responsible for hydrolyzing the neurotransmitter acetylcholine (ACh). AChE operates near diffusion control and can hydrolyze upwards of 25,000 ACh molecules every second. However, when AChE is inhibited by a nerve agent, an excess amount of ACh will build up at neurosynaptic gaps, thereby causing a cholinergic crisis. Once this occurs, a person will start to develop symptoms of muscle contractions, blurry vision, seizures and/or respiratory failure. An OP nerve agent has this effect because it is a structural analog to ACh; however, phosphylation of the active site is more difficult to reverse. Reactivation of AChE can occur by hydrolyzing the phosphylated enzyme with a nucleophile such as 2-PAM (often administered after OP exposure has occurred). Unfortunately, if this reactivation does not occur, the phosphylated enzyme will undergo a spontaneous dealkylation step (termed aging) to give a “dead” enzyme, which to date cannot be reactivated. The first therapeutic design focuses on the research and development of phosphorane haptens. These haptens are conjugated to some mutagen and administered into mice. This causes an immune response and can generate catalytic antibodies which are capable of hydrolyzing the nerve agent VX. In total, ten different haptens were synthesized, mimicking the hydrolysis transition state of VX, and all generated specific antibodies. Each titer of antibodies were then tested against authentic VX samples. The second approach focuses on the development of a combinatorial approach to synthesizing a random library of cyclic peptides. These cyclic peptides are meant to model the activ (open full item for complete abstract)

Committee: Christopher Hadad (Advisor); Jon Parquette (Committee Member); Psaras McGrier (Committee Member) Subjects: Chemistry