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1 Resurrection of Organophosphorus-Aged Acetylcholinesterase Via Mannich Bases Derived from Proline Thesis Presented in Partial

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1 Resurrection of Organophosphorus-Aged Acetylcholinesterase Via Mannich Bases Derived from Proline Thesis Presented in Partial Resurrection of Organophosphorus-Aged Acetylcholinesterase via Mannich Bases Derived from Proline Thesis Presented in Partial Fulfillment of the Requirements for the Degree Master of Science in the Graduate School of The Ohio State University By Nathan A. Ward Graduate Program in Chemistry The Ohio State University 2019 Thesis Committee Dr. Christopher M. Hadad, Advisor Dr. Jon R. Parquette, Member 1 Copyrighted by Nathan A. Ward 2019 2 Abstract Organophosphorus (OP) compounds are responsible for an estimated 220,000 deaths annually. OP compounds inhibit the enzyme acetylcholinesterase (AChE) via phosphylation of a serine residue within the active site. Upon inhibition of AChE, acetylcholine accumulates in neuromuscular junctions, resulting in a cholinergic crisis and, if not treated immediately, can lead to death. Along with management of symptoms, current medical countermeasures for OP poisoning utilize nucleophilic oximes, which can displace the phosphorus moiety from the serine residue, reactivating AChE to its native state. However, following inhibition, a spontaneous O-dealkylation of the phosphylated serine residue can occur, resulting in an anionic phosphylated serine residue; this process is known as aging. There is currently no approved therapeutic that is capable of restoring OP-aged AChE to its native state (a process referred to as resurrection). Previous studies by our group have shown that a class of compounds called quinone methide precursors (QMPs) both resurrect OP-aged AChE and reactivate OP- inhibited AChE back to its native state. A previous lead QMP from the Hadad group featured a pyrrolidine leaving group, while the current lead QMP features an (R)-2-methylpyrrolidine leaving group. Thus, the addition of a methyl group at the 2-position of the pyrrolidine ring with the (R)- configuration increased the resurrection efficacy of OP-aged AChE. This work describes the synthesis of novel QMPs that have been derived from proline. Proline was derivatized to vary the functional group at the 2-position of the pyrrolidine ring in an effort to further increase the resurrection efficacy of OP-aged AChE. iii More specifically, proline was derivatized to feature ester, amide, alcohol, ether, and amine functional groups. Then, the QMPs were synthesized via a Mannich reaction between 3-hydroxypyridine and the proline derivatives. The QMPs were screened against OP-aged AChE and the resurrection efficacy was measured via Ellman’s assay. iv Acknowledgments To all my friends and family who have supported me on this arduous journey: thank you. To my advisor, Dr. Christopher Hadad – thank you for giving me the opportunity to do research in your laboratory, and for the guidance you have provided over the past two years. To Dr. Christopher Callam – thank you for giving me the opportunity to teach organic chemistry recitation for you; it was an invaluable experience. Thank you for all the organic synthesis advice you have given me, as well. To everyone in the Hadad, Callam, and Dogan Ekici groups – thank you for being so supportive and for making the laboratory a fun place to work every day. To Curt Wong – thanks for being a good friend, and for all of the synthesis advice. Also, thanks for convincing me that I was being stupid every time I even thought about quitting graduate school. Finally, I’d especially like to thank my best friend and partner, Nicole González Salguero – I would never have gotten this far without your endless love and support. You’ve inspired and motivated me since the very first day of this journey. I love you. v Vita 2016…………………………………………B.S. Chemistry (ACS Certified), Northern Kentucky University 2016 – 2017…………………………………HPLC Chemist, Advanced Testing Laboratory 2017 – 2019…………………………………Graduate Teaching Assistant, Department of Chemistry and Biochemistry, The Ohio State University Fields of Study Major Field: Chemistry vi Table of Contents Abstract ......................................................................................................................... iii Acknowledgments ........................................................................................................... v Vita ................................................................................................................................ vi List of Tables .............................................................................................................. viii List of Figures ................................................................................................................ ix Chapter 1: Introduction .................................................................................................... 1 Chapter 2: Mannich Base QMPs Derived from Proline Esters and Amides .................... 13 Chapter 3: Mannich Base QMPs Derived from Prolinol Ethers and Amines .................. 43 Chapter 4: Future Work ................................................................................................. 58 Bibliography ................................................................................................................. 61 Appendix: NMR Spectra ............................................................................................... 65 vii List of Tables Table 1.1 Aging half-times of various OP compounds.19 ................................................. 8 Table 2.1 Data for the resurrection (24 h) of DFP-aged recombinant human AChE with Mannich base QMPs derived from proline esters and amides. Each QMP was used at a 1 mM concentration at pH 7.5 and 37 °C. The standard deviation is derived from four replicate samples. Screening data for QMP-2.2 is shown for reference. N.D. = Not Determined. ................................................................................................................... 21 Table 3.1 Data for the resurrection of DFP-aged recombinant human AChE with Mannich base QMPs (1 mM, pH 7.5, 37 °C, 24 h) derived from prolinol. Screening data for QMP-2.2 is shown for reference. The negative control consisted of DFP-aged hAChE with no QMP. The positive control consisted of native hAChE. The standard deviation was determined from 4 replicate samples. ...................................................................... 44 viii List of Figures Figure 1.1 Chemical structures of DFP, PM, and PE. ...................................................... 1 Figure 1.2 Chemical structures of some common G-series and V-series nerve agents. .... 3 Figure 1.3 Mechanism of AChE-catalyzed hydrolysis of ACh. ....................................... 5 Figure 1.4 Common oximes used for the treatment of OP-inhibited AChE. ..................... 6 Figure 1.5 Mechanism of inhibition and aging of AChE by an OP compound. ................ 7 Figure 1.6 Resurrection of OP-aged AChE by QMPs. ..................................................... 9 Figure 2.1 The chemical structures of two lead Mannich base QMPs that are capable of resurrecting OP-aged AChE. ......................................................................................... 13 Figure 2.2 General synthesis route to make Mannich base QMPs based on various proline derivatives. ........................................................................................................ 15 Figure 2.3 General reaction scheme for the synthesis of Mannich base QMPs derived from various proline ester derivatives and the chemical structures of all synthesized ester variants. ......................................................................................................................... 16 Figure 2.4 General reaction scheme for the synthesis of some Mannich base QMPs derived from various proline amide derivatives and the chemical structures of the QMPs synthesized from this route. ........................................................................................... 18 Figure 2.5 Reaction scheme for the synthesis of Mannich base QMPs derived from L- prolinamide and D-prolinamide. .................................................................................... 19 Figure 2.6 The reactions of Ellman’s assay. .................................................................. 20 Figure 2.7 Resurrection of DFP-aged AChE with Mannich base QMPs derived from proline esters and amides. Screening data for QMP-2.5, QMP-2.7, and QMP-2.14 is still pending. ........................................................................................................................ 22 Figure 3.1 General reaction scheme for the synthesis of Mannich base QMPs derived from prolinol and the chemical structures for each variant synthesized. ......................... 43 Figure 3.2 Resurrection of DFP-aged AChE with Mannich base QMPs derived from prolinol. ......................................................................................................................... 45 Figure 3.3 General reaction scheme for the synthesis of Mannich base QMPs derived from various prolinol ether derivatives and the chemical structures of the QMPs synthesized from this route. ........................................................................................... 46 Figure 3.4 General reaction scheme for the synthesis of Mannich base QMPs derived from various prolinol amine derivatives and the chemical structures of the QMPs synthesized from this route. ........................................................................................... 48 Figure 4.1 Proposed scheme for synthesizing various Mannich base QMPs derived from alkylated pyrrolidines.
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