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Green Flourescent Protein Inspired Chromophore As Estrogen Receptor Agonist-Synthesis, Biological Evaluations and Cellular Application

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Green Flourescent Protein Inspired Chromophore As Estrogen Receptor Agonist-Synthesis, Biological Evaluations and Cellular Application GREEN FLOURESCENT PROTEIN INSPIRED CHROMOPHORE AS ESTROGEN RECEPTOR AGONIST-SYNTHESIS, BIOLOGICAL EVALUATIONS AND CELLULAR APPLICATION A Dissertation Presented to The Academic Faculty by Christopher L. Walker In Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the School of Chemistry and Biochemistry Georgia Institute of Technology May 2019 COPYRIGHT © 2019 BY CHRISTOPHER L. WALKER GREEN FLUORESCENT PROTEIN INSPIRED CHROMOPHORE AS ESTROGEN RECEPTOR AGONIST-SYNTHESIS, BIOLOGICAL EVALUATIONS AND CELLULAR APPLICATION Approved by: Dr. Loren Williams, Advisor Dr. Terry Snell School of Chemistry and Biochemistry School of Biology Georgia Institute of Technology Georgia Institute of Technology Dr. Charles L. Liotta Dr. Bahareh Azizi School of Chemistry and Biochemistry Kuwait Foundation for the Georgia Institute of Technology Advancement of Sciences Dr. Adegboyega Oyelere School of Chemistry and Biochemistry Georgia Institute of Technology Date Approved: [October 01, 2018] Dedicated to my mother and father for their endless sacrifice ACKNOWLEDGEMENTS No journey is successful because of the efforts of one individual but the community that supports the goal. I am grateful to the people who have supported my journey through graduate school. I’m thankful to my advisors Dr. Loren Williams and Dr. Bahareh Azizi for not only your support and mentorship but your guidance, patience and direction. I appreciate your unwavering commitment to helping me grow as a scientist and individual, you have offered your support as life has continually changed and for that I’m grateful. In addition to my advisors the leadership and mentoring of various faculty and administrators at Georgia Tech has been outstanding with that I would like to thank Dr. Charles Liotta, Dr. Cam Tyson and Dr. Keith Oden. I appreciate the insightful conversations provided by Dr. Liotta working as a teacher’s assistant under you for 3 years allowed me the chance to develop my own style as a teacher. Dr. Tyson thank you for your continually support and concern your assistance through ever transition during graduate school was appreciated. Dr. Oden thank you for your guidance, mentorship and friendship I reverence our time spent together and the lessons imparted to me during that time thank you for giving of yourself and your experiences. In addition to the community at Georgia Tech that has supported me, my friends and family have embraced my process and journey as if it were their own. My most sincere appreciation goes to my brothers Santino, Rico and Isaac thank you for the supportive conversations, words of encouragement and belief in me this accomplishment is just as much a testament to persistence as it is to your friendship. I would also like to thank my parents who have given everything of themselves to support any dream that I could imagine since a child. As parents you both have loved and encouraged me through every phase of life, thank you for every lesson taught, for exemplifying v a hard work ethic, for demonstrating what the process looks like. There are no words that can express my true gratitude for what you have done and what you mean to me I am honored to be your son. To my own family, my wife and son thank you for always being the reason “why”. To my wife this has been an amazing journey thank you for your support and willingness to partake in the adventure with me. To my son thank you for being everything, my heart, my laughter and joy time spent with you is the highlight of everyday and while this is a milestone accomplishment having you is the greatest accomplishment of all. Thank you for your understanding and encouragement while at the moment age does not provide you with the understanding to grasp why “dads school work” takes me away from moments as you get older hopefully you will comprehend this was about teaching you to finish what you start and early insight to what the “process” looks like. Lastly to my grandmother Ollie May Jackson and my friend Dina Reynolds thank you for being there in the beginning of this process I only wish you could be here to see the ending. Thank you for the lasting contributions you made into my life. I miss you both every day, your love, friendship and past conversations guide me even today. Grandmother I cherish the memories and hold the moments as precious and yes in all things including this body of work “To God be the glory”. vi TABLE OF CONTENTS ACKNOWLEDGEMENTS v LIST OF TABLES xxi LIST OF FIGURES xii LIST OF SYMBOLS AND ABBREVIATIONS xxv SUMMARY xxix CHAPTER 1. Overview and Summary 1 1.1 Motivation 1 1.1.1 Designing of a potent estrogen receptor agonist 3 1.1.2 Promoting selectivity within isotypes and among nuclear receptors 4 1.1.3 Accessing the role of florescence and activation 5 1.2 References 7 CHAPTER 2. Green Fluorescent Protein 8 2.1 Historical Perspective 8 2.2 Green Flourescent Protein 9 2.2.1 Green Flourescent Protein Discovery 11 2.2.2 Green Flourescent Protein Structure 12 2.3 Synthesis of GFP Chromophore 13 2.4 GFP Photochemical Properties 15 2.5 Fluorescent Proteins 16 2.6 References 17 CHAPTER 3. Nuclear Receptors 19 3.1 Nuclear Recptors Overview 19 3.2 Nuclear Receptor Structure (Regions and Domains) 21 3.2.1 Activation transcription factor (AF-1) 22 3.2.2 DNA binding domain 23 3.2.3 Ligand binding domain 23 3.2.4 Activation transcription factor (AF-2) 24 3.3 Nuclear Receptor Domain Function 24 3.3.1 Activation Transcription Facrtor-1 (AF-1) 24 3.3.2 DNA binding domain 24 3.3.3 Hormone response element 25 3.3.4 Hinge 25 3.3.5 Ligand binding domain 25 3.3.6 Activation Transcription Factor-2 (AF-2) 25 3.4 Nuclear Receptor Ligands 26 3.4.1 Agonist 26 vii 3.4.2 Antagonist 28 3.5 Mechanism of Ligand Mediated Receptors 29 3.5.1 Apo 30 3.5.2 Halo 31 3.6 Nuclear Receptors Role in Diseases 31 3.6.1 Estrogen Receptor 32 3.6.2 Peroxisome Proliferator- Activated Receptor gamma 33 3.7 Nuclear Receptors Role as Pharmacutical Targets 33 3.8 References 36 CHAPTER 4. Synthesis of GFP Chromophore Inspired Ligands as Estrogen Receptor Alpha Agonist 39 4.1 Estrogen Receptor 39 4.1.1 Estrogen Receptor Alpha 39 4.1.2 Ligand Binding Pocket 40 4.1.3 Ligands 41 4.2 Estrogen Receptor Ligand Design Rationale 43 4.2.1 Hydrogen Bonding Network 46 4.2.2 Ligand Volume and Size 47 4.2.3 Molecular Topology 48 4.3 Synthesis of Arylmethyleneimidazolone 50 4.4 Arylmethyleneimidazolone Chromophore Properties 54 4.5 Biological Assay Screens 56 4.5.1 Chemical Complementation 56 4.5.2 Chemiluminescence 57 4.5.3 Nuclear Receptors and Reporter Gene Assay 57 4.6 Generation I Results 60 4.6.1 Chemical Complementation 61 4.6.2 Luciferase Results 62 4.6.2.1 Hydrogen Bonding Network 65 4.6.2.2 Molecular Topography 67 4.6.2.3 Ligand Volume 69 4.7 Structure Activity Relationships Compounds 71 4.7.1 A-Ring 71 4.7.2 Core-Scaffold 71 4.7.3 D-Ring 72 4.7.4 Hydrogen Bonding Network 72 4.7.5 Ligand Volume and Size 73 4.7.6 Molecular Topology 73 4.8 Generation II Results 74 4.8.1 Chemical Complementation 74 4.8.2 Luciferase Assay 75 4.8.2.1 Hydrogen Bonding Network 75 4.8.2.2 Ligand Volume-Size 76 4.8.2.3 Molecular Topology 76 4.9 Ligand Activation Rationale 80 viii 4.9.1 Hydrogen Bonding Network 81 4.9.2 Ligand Volume (Shape/Size) 84 4.9.3 Molecular Topology-ACD ring effectiveness 86 4.10 Summary 89 4.11 Materials and Methods 90 4.12 References 94 CHAPTER 5. Investigating Selectivity Within Estrogen Receptor Beta And The Nuclear Receptor Family 98 5.1 Estrogen Reecptor Beta 99 5.1.1 Ligand Binding Pocket 99 5.1.2 Ligands 100 5.1.2.1 Selective Ligands 101 5.1.3 Physiological Role of Estrogen Receptor Beta 103 5.2 Design for Selectivity 104 5.2.1 ACD 105 5.2.2 Chirality 105 5.3 Chemical Complementation 107 5.3.1 Estrogen Receptor alpha Active Lignads 107 5.3.2 AMI Library Screen 108 5.3.3 Generation III Results(Chiral AMI Ligands) 109 5.4 Luciferin Reporter Assay Analysis fo Isotype Specificity 109 5.4.1 Estrogen Receptor alpha Active Ligands 109 5.4.2 AMI Library Screen 111 5.4.3 Generation III Results 111 5.5 Time Resolved Fluorescence Resonance Energy Transfer 112 5.6 Selective Ligand Activation Discussion Rationale 113 5.6.1 Hydrogen Bonding Network 114 5.6.2 Ligand Volume-Size and Shape 116 5.6.3 Molecular Topology 119 5.6.4 Chirality 120 5.7 Identification of Active Leads for Estrogen Receptor 120 5.8 Nuclear Receptor Selectivity 121 5.8.1 Rexinoid X Receptor Alpha 121 5.8.1.1 Ligand Binding Pocket Comparison 122 5.8.1.2 Rexinoid X Receptor Chemical Complementation Results 124 5.8.2 Retinoic Acid Receptor Gamma 125 5.8.2.1 Ligand Binding Pocket Comparison 125 5.8.2.2 Chemical Complementation Results 126 5.9 Summary 127 5.10 Materials and Methods 128 5.11 References 130 CHAPTER 6. Investigation Into Fluorescence and Binding 134 6.1 Nuclear receptor probes 134 6.1.1 Green Fluorescent Protein Fusion 135 ix 6.1.2 Classical Receptor Tracking 136 6.1.3 GFP Inspired Ligands as Nuclear Receptor Probes 138 6.2 GFP Inspired Ligands as Nuclear Receptor Probes In vivo 138 6.3 GFP Inspired Ligands as Nuclear Receptor Probes In vitro 141 6.4 Summary 144 6.5 Materials and Methods 144 6.6 References 144 CHAPTER 7.
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