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Design, Synthesis, Kinetic Analysis, Molecular Modeling, and Pharmacological Evaluation of Novel Inhibitors of Peptide Amidation

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Design, Synthesis, Kinetic Analysis, Molecular Modeling, and Pharmacological Evaluation of Novel Inhibitors of Peptide Amidation DESIGN, SYNTHESIS, KINETIC ANALYSIS, MOLECULAR MODELING, AND PHARMACOLOGICAL EVALUATION OF NOVEL INHIBITORS OF PEPTIDE AMIDATION A Thesis Presented to the Academic Faculty by Michael Scott Foster In Partial Fulfillment Of the Requirements for the Degree Doctor of Philosophy in Chemistry Georgia Institute of Technology December 2008 DESIGN, SYNTHESIS, KINETIC ANALYSIS, MOLECULAR MODELING, AND PHARMACOLOGICAL EVALUATION OF NOVEL INHIBITORS OF PEPTIDE AMIDATION Approved by: Dr. Sheldon W. May Dr. Stanley H. Pollock School of Chemistry and Biochemistry Pharmaceutical Sciences Georgia Institute of Technology Mercer University Dr. James C. Powers Dr. Niren Murthy School of Chemistry and Biochemistry School of Biomedical Engineering Georgia Institute of Technology Georgia Institute of Technology Dr. Nicholas V. Hud Date Approved: August 12, 2008 School of Chemistry and Biochemistry Georgia Institute of Technology For Dr. Sheldon W. May, without whose indefatigable kindness, patience, good humor, and positive attitude, I surely would never have completed this work. For Amanda, whose loyalty, love, and trust throughout these many years have ever been a blessing to me. For Dave, the best brother a person could ask for. And for my mother, who gave me everything. I am sorry you could not be here to share in my success. ACKNOWLEDGEMENTS I give, again, my deepest thanks to Dr. Sheldon May for the opportunity to work alongside him and with his group for these wonderful years. Also, many thanks to Dr. Charlie Oldham for listening to me gripe about ill-conceived software default settings and shoddy instrument engineering without every becoming more than mildly irritated with me. His encyclopedic knowledge of many different scientific and technical fields has been a wonderful benefit to my graduate career. I also wish to thank Dr. Stanley Pollock of Mercer University for allowing me to expand my research horizons into pharmacological studies. Thanks also to the following for various contributions to my knowledge, technique, and my general welfare: Dr. Kristi Burns, Dr. Veronica de Silva, Dr. Jennifer Overcast Lane, Dr. Jeffrey Sunman, Dr. John Bauer, Dr. Michael Kulis, Mr. Jeremy Thompson, Mr. Jacob Lucrezi, Ms. Elizabeth Cowan, and Ms. Maggie Schwab. I also wish to thank the other members of my Thesis Committee, Dr. James Powers, Dr. Nicholas Hud, and Dr. Niren Murthy. I appreciate the personal time that everyone has spent on my behalf. Finally, I would like to thank the National Institutes of Health (NIH) and the National Arthritis Foundation for their generous supports of the work presented herein. iv TABLE OF CONTENTS ACKNOWLEDGEMENTS iv LIST OF TABLES viii LIST OF FIGURES ix LIST OF ABBREVIATIONS xii SUMMARY xiv PART 1: DESIGN, SYNTHESIS, KINETIC ANALYSIS, AND MOLECULAR MODELING OF NOVEL INHIBITORS OF PEPTIDE AMIDATION CHAPTER 1: INTRODUCTION 1 General Introduction 1 PAM Localization and Expression 6 Substrates and Inhibitors 24 PAM Mechanism 45 CHAPTER 2: MATERIALS AND METHODS 59 TNP-D-Tyr-L-Val-Gly 59 TNP-D-Tyr-L-Val-(S)-α-Hydroxy-Gly (TNP-YV(OH)G) 59 N-Ac-(D)-Phe-Acrylate 60 N-Ac-(D)-Phe-OMe 61 N-Ac-(D)-Phe-α-Ketophosphonate 61 Methyl Glyoxylate 62 Methyl-N-Ac-(D)-Phe-Acrylate 63 N-Ac-(D)-Phe-Acrylic Acid 63 N-Ac-(L)-Phe-Acrylate 64 N-Ac-(L)-Phe-OEt 64 N-Ac-(L)-Phe-α-Ketophosphonate 65 Methyl-N-Ac-(L)-Phe-Acrylate 66 N-Ac-(L)-Phe-Acrylic Acid 66 Methyl-4-Phenyl-3-Butenoate 67 Spodoptera Frugiperd Cell Culture 67 Expression of X. Laevis Skin AE-1 68 Enzyme Isolation 68 Standard PAM Activity Assay 70 Dilution Assay 70 Progress Curve Assay 71 v Circular Dichroism Spectroscopy 71 HPLC Chiral Chromatography 72 PAM/Ligand Docking 72 Flexible Alignment 74 CHAPTER 3: RESULTS 75 PAM Isolation 75 Synthesis and Characterization of N-Ac-(L)/(D)-Phe-Acrylate 77 Inactivation Kinetics 84 Dilution Assay 87 Progress Curve Assay 99 PAM/Ligand Docking 126 CHAPTER 4: KINETICS AND MODELING DISCUSSION 164 PART 2: NOVEL INHIBITORS OF SUBSTANCE P 192 BIOACTIVATION AS POTENTIAL ANTI- INFLAMMATORY AND ANTI-NEOPLASTIC AGENTS CHAPTER 5: INTRODUCTION 193 General Introduction 193 Substance P and Neurokinin Expression 199 Protein Kinase C and Downstream Cellular Signaling 201 Nuclear Factor κB (Nuclear Factor κB) 202 Effects of Substance P on Cells of the Immune System 206 Substance P and Apoptosis 213 CHAPTER 6: MATERIALS AND METHODS 217 Animals 217 Reagents 217 Preparation and Administration of PBA and APAA-OMe 218 Collection of Blood/Serum from Sprague/Dawley Rats 218 Analysis of Serum PAM Activity 219 Induction of Adjuvant Arthritis and Carrageenan Edema 219 WB-Neo and WB-Ras Cell Culture and PAM Activity 220 Statistical Analysis 221 CHAPTER 7: RESULTS 222 Effect of PBA on Serum PAM Activity in vivo 224 Effect of N-Ac-(L)-Phe-Acrylate on Serum PAM Activity 226 Effect of Methyl-N-Ac-(L)-Phe-Acrylate on Serum PAM Activity 229 Acute Anti-Inflammatory Effect of APAA-OMe 232 Effect of APAA-OMe on Adjuvant-Induced Polyarthritis (AIP) 235 PAM Activity in WB-Neo Cells and Inhibition by PBA 237 PAM Activity in WB-Ras Cells and Inhibition by PBA 239 vi Cultured WB-Neo and WB-Ras Cells: Inhibition by 240 PBA and PBA-OMe CHAPTER 8: DISCUSSION 243 REFERENCES 261 vii LIST OF TABLES Table 1. Isolation Table of PAM (AE-1) Expressed from Sf9 Cells 76 Table 2. Collected Kinetic Parameters from Dilution and Progress Curve 125 viii LIST OF FIGURES Figure 1. Reaction Scheme for PAM and PGL 25 Figure 2. Structures of Hippuric Acid Analogs 30 Figure 3. Cartoon of the X-Ray Structure of Oxidized PAM 35 Figure 4. Molecular Structures of Compounds Tested 57 Figure 5. Synthetis of N-Ac-Phe-Acrylate 79 Figure 6. Overlaid Circular Dichroism Spectra of N-Ac-(L)-Phe-Acrylate 81 Figure 7. Chromatogram of Methyl-N-Ac-(D)-Phe-Acrylate 82 Figure 8. Chromatogram of Methyl-N-Ac-(L)-Phe-Acrylate 83 Figure 9. Possible Mechanistic Pathways for Mechanism-Based Inactivators 85 Figure 10. Semi-Log Plot of Percent Initial Activity vs. Time ((L)-Phe-Acrylate) 90 Figure 11. Kitz/Wilson Double-Reciprocal Plot (N-Ac-(L)-Phe-Acrylate) 92 Figure 12. Semi-Log Plot of Percent Initial Activity vs. Time ((D)-Phe-Acrylate) 94 Figure 13. Kitz/Wilson Double-Reciprocal Plot (N-Ac-(D)-Phe-Acrylate) 95 Figure 14. Semi-Log Plot of Percent Initial Activity vs. Time ((L)-Met-Acrylate) 98 Figure 15. Kitz/Wilson Double-Reciprocal Plot (N-Ac-(L)-Met-Acrylate) 99 Figure 16. Product Concentration vs. Time (N-Ac-(L)-Phe-Acrylate) 108 Figure 17. Plot of [TNP-YV(OH)G]∞ vs. 1/[N-Ac-(L)-Phe-Acrylate] 109 Figure 18. Plot of 1/slope vs. 1/[TNP-YVG] (N-Ac-(L)-Phe-Acrylate) 110 Figure 19. Plot of 1/kobs vs. 1/[N-Ac-(L)-Phe-Acrylate] 111 Figure 20. Ratio of y-Intercept/Slope vs. [TNP-YVG]/(Km + [TNP-YVG]) 112 Figure 21. Product Concentration vs. Time (N-Ac-(D)-Phe-Acrylate) 113 ix Figure 22. Plot of [TNP-YV(OH)G]∞ vs. 1/[N-Ac-(D)-Phe-Acrylate] 114 Figure 23. Plot of 1/slope vs. 1/[TNP-YVG] (N-Ac-(D)-Phe-Acrylate 115 Figure 24. Plot of 1/kobs vs. 1/[N-Ac-(D)-Phe-Acrylate] 116 Figure 25. Ratio of y-Intercept/Slope vs. [TNP-YVG]/(Km + [TNP-YVG]) 117 Figure 26. Product Concentration vs. Time (N-Ac-(L)-Met-Acrylate) 118 Figure 27. Plot of [TNP-YV(OH)G]∞ vs. 1/[N-Ac-(L)-Met-Acrylate] 119 Figure 28. Plot of 1/slope versus 1/[TNP-YVG] (N-Ac-(L)-Met-Acrylate) 120 Figure 29. Plot of 1/kobs versus 1/[N-Ac-(L)-Met-Acrylate] 121 Figure 30. Ratio of y-Intercept/Slope vs. [TNP-YVG]/(Km + [TNP-YVG]) 122 Figure 31. Hanes-Woolf Plot of [TNP-YVG]/v vs. [TNP-YVG] w/KI 123 Figure 32. Hanes-Woolf Plot of [TNP-YVG]/v vs. [TNP-YVG] w/o KI 124 Figure 33. IYG Docked to PAM Active Site 133 Figure 34. N-Ac-(L)-Phe-Gly Docked to PAM Active Site 136 Figure 35. N-Ac-(D)-Phe-Gly Docked to PAM Active Site 137 Figure 36. N-Ac-(L)-Leu-OCH2-COOH Docked to PAM Active Site 140 Figure 37. N-Ac-(D)-Leu-OCH2-COOH Docked to PAM Active Site 142 Figure 38. N-Ac-(L)-Phenylglycine-Gly Docked to PAM Active Site 144 Figure 39. O-Ac-(R)-Mandelyl-Gly Docked to PAM Active Site 145 Figure 40. N-Ac-(L)-Phe-Acrylate Docked to PAM Active Site 147 Figure 41. N-Ac-(D)-Phe-Acrylate Docked to PAM Active Site 148 Figure 42. N-Ac-(L)-Met-Acrylate Docked to PAM Active Site 151 Figure 43. N-Ac-(D)-Met-Acrylate Docked to PAM Active Site 152 Figure 44. N-Ac-(L)-2’-Thienyl-Acrylate Docked to PAM Active Site 154 x Figure 45. N-Ac-(D)-2’-Thienyl-Acyrlate Docked to PAM Active Site 155 Figure 46. N-Ac-(L)-Phe-Crotonate Docked to PAM Active Site 157 Figure 47. N-Ac-(D)-Phe-Crotonate Docked to PAM Active Site 158 Figure 48. N-Ac-(L)-Phe-Propiolate Docked to PAM Active Site 160 Figure 49. N-Ac-(D)-Phe-Propiolate Docked to PAM Active Site 161 Figure 50. PBA Docked to PAM Active Site 162 Figure 51. Flexible Alignment Overlay of N-Ac-(L)-Phe-Gly and 175 N-Ac-(L)-Phe-Acrylate Figure 52. Flexible Alignment Overlay of N-Ac-(L)-Phe-Gly and 176 N-Ac-(D)-Phe-Gly Figure 53. Flexible Alignment Overlay of N-Ac-(L)-Phe-Gly and 177 N-Ac-(D)-Phe-Acrylate Figure 54.
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