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Exploring the Interaction Between Asymmetric Phosphonates and Acetylcholinesterase. Probing the Gorge and P-Site Via Customized Covalent Modification

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Exploring the Interaction Between Asymmetric Phosphonates and Acetylcholinesterase. Probing the Gorge and P-Site Via Customized Covalent Modification University of Montana ScholarWorks at University of Montana Graduate Student Theses, Dissertations, & Professional Papers Graduate School 2008 Exploring the interaction between asymmetric phosphonates and acetylcholinesterase. Probing the gorge and P-site via customized covalent modification Lilu Guo The University of Montana Follow this and additional works at: https://scholarworks.umt.edu/etd Let us know how access to this document benefits ou.y Recommended Citation Guo, Lilu, "Exploring the interaction between asymmetric phosphonates and acetylcholinesterase. Probing the gorge and P-site via customized covalent modification" (2008). Graduate Student Theses, Dissertations, & Professional Papers. 421. https://scholarworks.umt.edu/etd/421 This Dissertation is brought to you for free and open access by the Graduate School at ScholarWorks at University of Montana. It has been accepted for inclusion in Graduate Student Theses, Dissertations, & Professional Papers by an authorized administrator of ScholarWorks at University of Montana. For more information, please contact [email protected]. EXPLORING THE INTERACTION BETWEEN ASYMMETRIC PHOSPHONATES AND ACETYLCHOLINESTERASE. PROBING THE GORGE AND P-SITE VIA CUSTOMIZED COVALENT MODIFICATION. By Lilu Guo B.S., Peking University, Beijing, P.R.China, 2000 Dissertation presented in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry The University of Montana Missoula, MT Summer 2008 Approved by: Dr. Perry Brown, Associate Provost Graduate School Dr. Charles M. Thompson, Chair Department of Biomedical & Pharmaceutical Sciences Dr. Mark Cracolice Department of Chemistry Dr. C. Sean Esslinger Department of Biomedical & Pharmaceutical Sciences Dr. J.B. Alexander (Sandy) Ross Department of Chemistry Dr. Holly Thompson Department of Chemistry © COPYRIGHT by Lilu Guo 2008 All Rights Reserved Guo, Lilu, PhD., Summer 2008 Chemistry Exploring the interaction between asymmetric phosphonates and acetylcholinesterase. Probing the gorge and P-site via customized covalent modification. Chairperson: Charles M. Thompson Organophosphates (OPs) react with acetylcholinesterases (AChEs) to form a covalent bond at a specific serine residue in the active gorge, thereby providing a highly precise modification of this enzyme and an opportunity to explore protein structure, function and mechanism. The goal of this study is: 1) to show how covalent modification of AChEs by chromophore-linked OPs can be used to probe the active and peripheral sites of the protein and its local environment; 2) to differentiate AChE stereoselectivity with asymmetric phosphonothiolates. Click chemistry was used as a key transformation method to prepare an array of chromophores linked to a reactive fluorophosphonate (FP) head group. Chromophore- linked FPs varying in length and chromophore were synthesized and computer-modeled to visualize and calculate positioning of the chromophore-FP-AChE relative to the protein active gorge. The inhibition rates of chromophore-FPs against recombinant mouse AChE (rMAChE) and electric eel AChE (EEAChE) were determined via colorimetric assay and the dansyl containing FPs were demonstrated to be the most potent. In addition, the binding effects of the chromophore and FP moiety to protein were evaluated and results demonstrated that the size and structure of chromophore and the length of the ligands mutually affect the inhibition potency. Dansyl, dabsyl and pyrene were the best chromophores with least interaction with AChEs. To examine the interactions of asymmetric analogs of the OP compounds within the steric confines of AChEs, the synthesis of phosphonothiolate enantiomers as anti-AChEs was conducted using a chiral auxiliary for separation. X-ray analysis and 31P NMR were used to show an exclusively separation of the two diastereomers. The kinetic parameters ki and KD for the inhibition of recombinant human AChE (rHuAChE) were determined. 3 - A 4-fold difference in anti-AChE potency was observed between Sp (ki = 1.7 x 10 M 1 -1 3 -1 -1 min ) and Rp (ki = 9.0 x 10 M min ). These enantiomers link to the chromophores via click reaction to form chromophore-linked asymmetric phosphonothiolates (CLAPs), which can be used to study AChE stereospecificity. ii ACKNOWLEDGEMENTS Firstly and most importantly, I would like to acknowledge my advisor, Professor. Charles M. Thompson for everything he has done for me. His expertise on organophosphorus makes my life much easier. Whenever I need suggestions or help, he is always available. I really appreciate for his continual support and faith in me. His kind words of wisdom, encouragement, endless hours of dedication to this project and me is invaluable. I would like to thank my committee: Dr. Mark Cracolice, Dr. Sean Esslinger, Dr. Sandy Ross, and Dr. Holly Thompson. They give me great advice during my progressive reviews and are always supportive. I am also grateful to the whole Thompson lab for all kinds of help during the last five years, with especially thanks to Dr. Alirica Suarez for her collaboration and Dr. Joseph Degraw for his sage advice on bench. I feel like to, and necessary to, express my sincerest regards to my dearest parents and brother. It is important for me to know that they’ll stand by me whatever happens and we are proud of each other. I also need to thank all of my friends who have been constantly giving me support. Lastly, I reserve my deepest thanks for the most important person in my life: my amazing boyfriend Ran, who has been influencing and fulfilling my life for many years. I would never come to where I am now without his love, support and confidence. His sweet smiles brighten my day and his love makes every moment more enjoyable and memorable. Dedicated to my parents, Tingxuan Guo & Guiyun Lei. iii TABLE OF CONTENTS LIST OF ABBREVIATIONS..........................................................................................viii LIST OF FIGURES ............................................................................................................ x LIST OF SCHEMES......................................................................................................... xv LIST OF TABLES.......................................................................................................... xvii CHAPTER 1. INTRODUCTION .......................................................................................................... 1 2. BACKGROUND ............................................................................................................ 5 2.1 ACh, AChE and the Cholinergic System .......................................................... 5 2.2 Structural and Mechanistic Features of AChE.................................................. 8 2.3 AChE Hydrolysis of ACh................................................................................ 13 2.4 Organophosphorus Compounds (OPs)............................................................ 15 2.5 Mechanism and Kinetics of AChE Inactivation by OPs ................................. 19 2.6 Post-inhibition Phase of AChE Inhibited by OPs ........................................... 23 2.6.1 Spontaneous Reactivation....................................................................... 23 2.6.2 Oxime-Mediated Reactivation................................................................ 24 2.6.3 Aging and Non-reactivation.................................................................... 26 2.7 Stereochemical Aspects of Organophosphorus Compounds........................... 28 2.8 Mechanism and Kinetics of AChE Inactivation by Reversible Inhibitors ...... 31 2.9 OP-Tethered Reporter Groups......................................................................... 35 2.10 Click Chemistry............................................................................................... 42 2.11 Single Molecule Docking and FlexX .............................................................. 44 iv 3. OBJECTIVES............................................................................................................... 47 4. SYNTHESIS................................................................................................................. 48 4.1 Chromophore-linked Fluorophosphonates (FPs) ............................................ 48 4.1.1 Dansyl-linked Fluorophosphonates (FPs)............................................... 49 4.1.2 Other Chromophore-linked FPs.............................................................. 54 4.2 Dansyl-linked Phosphonothiolates.................................................................. 57 4.2.1 Synthetic Approach A: Conversion of P=O to P=S in 4a with Lawesson Reagent (LR)............................................................................................. 58 4.2.2 Synthetic Approach B: Reacting Bromo/Azo-phosphonates (Compound 1a or 2a) with LR...................................................................................... 60 4.2.3 Synthetic Approach C: Using Sodium Hydrosulfide (NaSH) As a Nucleophile to Produce Phosphonothioic Acids [P(O)SH]...................... 60 4.2.4 Synthetic Approach D: Using a New Synthesis Strategy Starting with Dimethyl Thiophosphite ........................................................................... 61 4.2.5 Summary................................................................................................. 65 4.3 Asymmetric Phosphonothiolates..................................................................... 66 4.3.1 Attempted Synthesis
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