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1 Reactivation and Resurrection of Organophosphorus Poisoned Reactivation and Resurrection of Organophosphorus Poisoned Acetylcholinesterase with Improved Methods of Detection Thesis Presented in Partial Fulfillment of the Requirements for the Degree Master of Science in the Graduate School of The Ohio State University By Stacey Katherine Allen Graduate Program in Chemistry The Ohio State University 2020 Thesis Committee Christopher M. Hadad, Advisor Thomas J. Magliery, Committee Member 1 Copyrighted by Stacey Katherine Allen 2020 2 Abstract The inhibition of acetylcholinesterase (AChE) by organophosphorus (OP) nerve agents and pesticides is, thankfully, reversible with the treatment of reactivators, such as 2-pralidoxime (2-PAM). However, if treatment is not administered quickly or if the OP is particularly toxic, these reactivators are rendered useless. After inhibition by an OP, a subsequent dealkylation event can occur at the phosphylated serine residue of AChE. This aged state of the enzyme cannot be revived by reactivators, and there are currently no approved treatments for the aged form of AChE. The aged form of AChE from OP poisoning was considered irreversible until 2018, when our team demonstrated the only compounds that are capable of reviving, or resurrecting, the aged form of electric-eel AChE using quinone methide precursors (QMPs). Inspired by this initial set of QMPs, a variety of 2-(aminomethyl)-3- hydroxypyridine QMPs were tested in vitro against inhibited and aged forms of recombinant human AChE that resemble the erythrocyte (dimer) and readthrough (monomer) isoforms. A modified Ellman’s assay, utilizing the artificial AChE substrate acetylthiocholine (ATC) and 5,5-dithio-bis-(2-nitrobenzoic acid) (DTNB), was used to detect the reappearance of native AChE during these studies. After 24 hours, up to 100% of the aged enzyme was resurrected for each isoform with select QMPs and also for specific OP compounds. The same QMP framework is also iii an effective treatment for OP-inhibited AChE and can reactivate up to 70% of recombinant human (erythrocyte) AChE and 20% of the readthrough isoform. Although these QMPs are not as efficient with reactivation as 2-PAM, their lack of a permanent charge makes them more efficient at crossing the blood-brain barrier. QMPs, acting as both a reactivator and a resurrector, will help pave the way to new, more effective treatments for OP poisoning. This dissertation presents comparative in vitro assays with both isoforms of the enzyme as well as the reactivation and resurrection efficiency with various QMPs in a structure-activity relationship library. To perform in vitro studies that are more representative of a human’s natural AChE, whole blood will be used in resurrection and reactivation studies of the most effective QMPs. Unfortunately, whole blood absorbs at a variety of wavelengths, limiting the practicality of Ellman’s assay. Therefore, new methods of detection must be explored; a variety of absorbance and fluorescence methods for detecting reactivated and resurrected native AChE will be presented herein. iv Vita 2020……….………………………………………………….Graduate Research Assistant The Ohio State University May 27 – June 2, 2020…………………………………………Virtual Science Day Judge The Ohio Academy of Science State Science Day 2018-2019……………………………………………………………....Teaching Assistant The Ohio State University 2018……………………………………………………….Master of Science in Chemistry University of North Carolina Wilmington 2016-2017………..….……………………………………….Graduate Research Assistant University of North Carolina Wilmington 2015-2017……………………………………………………………....Teaching Assistant University of North Carolina Wilmington 2015….………………………………….………………Bachelor of Science in Chemistry Minor in Psychology University of North Carolina Wilmington 2014-2015………..…………………………………….Undergraduate Research Assistant University of North Carolina Wilmington 2013-2015………....………………………………………Certified Pharmacy Technician CVS Pharmacy v Publications McGorry, R. J.; Allen, S. K.; Pitzen, M. D.; Coombs, T. C. Tetrahedron Lett. 2017, 58 (49), 4623–4627. https://doi.org/10.1016/j.tetlet.2017.10.063. Allen, S. K.; Lathrop, T. E.; Patel, S. B.; Harrell Moody, D. M.; Sommer, R. D.; Coombs, T. C. Tetrahedron Lett. 2015, 56 (44), 6038–6042. https://doi.org/10.1016/j.tetlet.2015.09.051. Fields of Study Major Field: Chemistry vi Table of Contents Abstract .............................................................................................................................. iii Vita ...................................................................................................................................... v List of Tables ................................................................................................................... viii List of Figures .................................................................................................................... ix Chapter 1. Introduction ....................................................................................................... 1 Chapter 2. Reactivation of Organophosphorus-Inhibited Acetylcholinesterase with Quinone Methide Precursors............................................................................................. 10 Introduction ................................................................................................................... 10 Results and Discussion ................................................................................................. 24 Experimental ................................................................................................................. 38 Chapter 3. Resurrection of Organophosphorus-Aged Acetylcholinesterase with Quinone Methide Precursors ........................................................................................................... 42 Introduction ................................................................................................................... 42 Results and Discussion ................................................................................................. 49 Experimental ................................................................................................................. 61 Chapter 4. Methods for Detecting Native Acetylcholinesterase ....................................... 65 References ......................................................................................................................... 72 vii List of Tables Table 1 Rates of Inhibition of Acetylcholinesterase by Various Organophosphorus * Chemical Nerve Agents and Pesticides. .......................................................................... 10 o Table 2 IC50 (μM) measurements (25 C, pH 7.5) of native rhuAChE (973 units of enzyme activity) and CP-AChE (354 units of enzyme activity) for several QMPs. ...................... 28 Table 3 Aging of Acetylcholinesterase by Organophosphorus Nerve Agents and * Pesticides. ........................................................................................................................ 43 Table 4 Binding affinity (Km) and molar extinction coefficients (ε) of acetylcholine (ACh), acetylthiocholine (ATCI), 5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB), and photometric compounds 44-48. ............................................................................................................. 70 viii List of Figures Figure 1 G-series organophosphorus nerve agents. ........................................................... 2 Figure 2 Simplified catalytic hydrolysis of acetylcholine (ACh) by acetylcholinesterase (AChE). ............................................................................................................................... 3 Figure 3 Isoforms of AChE (image reproduced from Ref. 7 and 8). ................................. 4 Figure 4 Catalytic triad of AChE (S203, H447, E334), oxyanion hole (G121, G122, A204), and choline-binding pocket (E202, W86).1......................................................................... 4 Figure 5 Membrane anchors for AChE (image reproduced from Ref. 9). ......................... 5 Figure 6 Inhibition of AChE by sarin (GB). ...................................................................... 6 Figure 7 V-series organophosphorus nerve agents. ........................................................... 7 Figure 8 Organophosphorus pesticides. ............................................................................. 8 Figure 9 Parties to the Geneva Protocol.11 ......................................................................... 9 Figure 10 Structures of currently approved treatments for OP poisoning: atropine (1), nicotinhydroxamic acid (2), 2-pralidoxime chloride (2-PAM, 3), and diazepam (4). ...... 14 Figure 11 Reactivation of sarin-inhibited AChE by an oxime......................................... 14 Figure 12 Irreversible aging of AChE through O-dealkylation. ...................................... 16 Figure 13 Crossing the blood-brain barrier (image reproduced from Ref. 30). ............... 17 Figure 14 Other permanently charged oxime reactivators. .............................................. 18 ix Figure 15 Uncharged oxime reactivators. ........................................................................ 19 Figure 16 Non-oxime reactivators. .................................................................................. 20 Figure 17 Reactivation of sarin-inhibited AChE by ADOC (10). ................................... 21 Figure 18 ADOC derivatives as reported by Cerasoli (11-14)38 and de Koning (15-18).39 ..........................................................................................................................................
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