Seton Hall University eRepository @ Seton Hall Seton Hall University Dissertations and Theses Seton Hall University Dissertations and Theses (ETDs) Spring 5-15-2017 Synthesis and Evaluation of A Novel Carbohydrate Template and Analogs Thereof for Potential CNS- active Drugs Emi Hanawa-Romero [email protected] Follow this and additional works at: https://scholarship.shu.edu/dissertations Part of the Carbohydrates Commons, Medicinal Chemistry and Pharmaceutics Commons, and the Organic Chemicals Commons Recommended Citation Hanawa-Romero, Emi, "Synthesis and Evaluation of A Novel Carbohydrate Template and Analogs Thereof for Potential CNS-active Drugs" (2017). Seton Hall University Dissertations and Theses (ETDs). 2279. https://scholarship.shu.edu/dissertations/2279 Synthesis and Evaluation of A Novel Carbohydrate Template and Analogs Thereof for Potential CNS-active Drugs by Emi Hanawa-Romero Submitted in partial fulfillment of the requirements for the degree Doctor of Philosophy Department of Chemistry and Biochemistry Seton Hall University May 2017 i © 2017 Emi Hanawa-Romero ii Acknowledgements I am very much thankful to my mentor, Prof. Cecilia Marzabadi, for her support and guidance, throughout the program. Her mentorship filled with enormous experience and knowledge, as well as her pleasant personality made this dissertation happen. She has always been there for me, whenever I encounter problems, and her perpetual encouragement made may PhD years consequential and enjoyable. I am grateful to the Department of Chemistry and Biochemistry for providing me the opportunity to pursue my PhD in Chemistry. I would also like to thank Prof. James Hanson and Fr. Gerald Buonopane for their support and encouragement. Their advices improved my understanding in science and the quality of my work for the entirely. I always enjoyed listening to the stories behind chemistry and science that are provide from Prof. Hanson and Fr. Gerry. I am also grateful to the opportunity to teach under Prof. Marzabadi and Prof. Hanson in organic chemistry lab. I am thankful to the Center for Applied Catalysis at Seton Hall University, especially Prof. Robert Augustine and Dr. Setrak Tanielyan, for their expertise and providing a special facility to conduct some reactions. I would also like to acknowledge Prof. Murphy, Prof. Gorun and Prof. Sabatino with the maintenance of NMR facilities. I am also thankful to Ms. Maureen Grutt, Mr. David Edwards and Mr. Rafael Rivera for their assistance. I am also grateful for Robert DeSimone Graduate Fellowship for partial financial support. I would like to acknowledge that receptor binding profiles, agonist and/or antagonist functional data and Ki determinations were generously provided by the National Institute of Mental Health's Psychoactive Drug Screening Program, Contract # iv HHSN-271-2013-00017-C (NIMH PDSP). The NIMH PDSP is Directed by Bryan L. Roth MD, PhD at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscoll at NIMH, Bethesda MD, USA. High resolution mass spectrometry was performed at Mass Spectroscopy Laboratory at University of Illinois at Urbana- Champaign, Urbana, IL, USA. I am particularly thankful to the director at MS lab, Mr. Furong Sun, for prompt support and the effort to solve problems in a timely manner, when I inquired. I could not have completed this dissertation without immeasurable support of my family and friends. Notably, I would like to thank my parents Munenori and Toyoko, for supporting my dream and encouraging me for every single decision I made. I would also like to thank my brother Akihito, my father-in-law Ricardo, my uncles Michael and Jerome Frank, my aunts Molly and Helen Frank for all their support. Last, but certainly not least, I would like to thank my husband Paul. He supported me from my early year in this program until the very end. I am incredibly grateful to his understanding in regard to my passion in science and irregular schedule associated with chemistry. Coming home to receive warm welcomes every day from Paul as well as Leo, Rusty, Argos and Gizmo assisted me to go through rough days and made this dissertation happen. v Table of Contents Acknowledgements iv List of Tables viii List of Schemes ix List of Figures xi Abbreviations xiv Abstract xix Chapter 1. An Introduction to Central Nervous System Disorders and the Drugs Used to Treat Them 1.1. Introduction 1 1.2. Addiction 11 1.3. Epilepsy 14 1.4. Parkinson’s Disease 19 1.5. CNS-Active Drugs 24 1.6. Summary 30 Chapter 2. Synthesis of A Novel Carbohydrate Template and Its Analogs for the Treatment of Addiction, Epilepsy, Parkinson’s Disease and other CNS Disorders 2.1. Introduction 32 2.2. Background 37 vi 2.3. Results: Chemistry 39 2.4. Summary 74 Chapter 3. Evaluation of A Novel Carbohydrate Template and Its Analogs for the Treatment of Addiction, Epilepsy, Parkinson’s Disease and other CNS Disorders 3.1. Introduction 77 3.2. Background 85 3.3. Results: Physicochemical Properties 87 3.4. Results: Biological Activity and SAR Analysis 91 3.5. Summary 125 Chapter 4. Conclusions 4.1. Conclusions 127 Chapter 5. Experimental 5.1. Experimental 131 References 159 Appendix – NMR Spectra 177 vii List of Tables Table 2.1. Various reaction conditions for solution based benzylidenation of D-glucal with p-anisaldehyde dimethylacetal. Table 2.2. Results of Imine, Oxime and Hydrazone Derivatives. Table 2.3. Results of Acetalization/Ketalization Derivatives. Table 3.1. Calculated Physicochemical Properties of the Series of Novel Carbohydrate Benzylidene Derivatives. Table 3.2. Primary Binding Assay Results. Table 3.3. Primary Functional Results – mGluRs. viii List of Schemes Scheme 1.1. Biosynthesis of L-DOPA. Scheme 2.1. Syntheses of Tri-O-acetyl-D-glucal 15. Scheme 2.2. Synthesis of Compound 12. Scheme 2.3. Acid Catalyzed Reactions Associated with Benzylidenation of Glycals. Scheme 2.4. Attempts at Basic Benzylidenation. Scheme 2.5. An alternative synthetic route of benzylidene glycal. Scheme 2.6. A Novel Carbohydrate Template and Sites of Modifications. Scheme 2.7. Deoxy Derivatives. Scheme 2.8. Type II Ferrier Rearrangement Derivatives. Scheme 2.9. Synthesis of C3 Derivatives – Hydrophobic Modifications. Scheme 2.10. C3 Derivatives – Conjugated Ketone 46. Scheme 2.11. C3 Derivatives – Imines, Oximes and Hydrazones. Scheme 2.12. C3 Derivatives – Attempted Fluorinations. Scheme 2.13. C3 Derivatives – Attempted Synthesis of a Thioketone Derivative. Scheme 2.14. Attempted Formation of an Allal Derivative 58. Scheme 2.15. Syntheses of Galactal Derivatives. ix Scheme 2.16. Syntheses of Acetalization/Ketalization Derivatives. Scheme 2.17. Syntheses of Ether Derivatives. x List of Figures Figure 1.1. The Number of New Patients in the U.S. in 2013. Figure 1.2. Age-adjusted death rates for selected causes of death for all ages, by sex: United States, 2004-2014. Figure 1.3. The Number of Drugs Approved by the FDA in 2015. Figure 1.4. The FDA Approval Duration and Rate: CNS vs. non-CNS Drugs. Figure 1.5. Percentage of Total Disability-Adjusted Life Years (DALYs) Lost from Diseases. Figure 1.6. Structures of Methamphetamine, Caffeine and Methylphenidate. Figure 1.7. Structures of Tetrahydrocannabinol and Cannabidiol. Figure 1.8. General Structure of Benzodiazepine. Figure 2.1. Components of the Blood Brain Barrier. Figure 2.2. Markush Structures of Novel Cyclopropanated Carbohydrates. Figure 2.3. Structure of Lead Molecule 12. Figure 2.4. Structures of Morphine and Derivatives Thereof. Figure 3.1. Pentameric Structure of GABAA Receptor and Binding Sites. Figure 3.2. Examples of Ligands of GABAA Receptor. Figure 3.3. Examples of Ligands of mGluR5. xi Figure 3.4. Examples of Ligands of D2-like Dopamine Receptors and Norepinephrine Transporter. Figure 3.5. Examples of Ligands of Muscarinic Acetylcholine Receptors. Figure 3.6. Examples of Ligands of 5-HTs. Figure 3.7. Examples of Ligands of Sigma 2 Receptor. Figure 3.8. Secondary Binding Results – mGluR5. Figure 3.9. Secondary Functional Results – mGluR5. Figure 3.10. Structures of Compounds Used for mGluR5 Tests. Figure 3.11. Secondary Binding Results – D2-like Dopamine Receptors. Figure 3.12. Secondary Functional Results – D3. Figure 3.13. Secondary Functional Results – D4. Figure 3.14. Structures of Compounds Used for D2-like Receptors Test. Figure 3.15. Secondary Binding Result – NET. Figure 3.16. Structures of Compounds Used for NET Test. Figure 3.17. Secondary Binding Result – M2. Figure 3.18. Secondary Binding Result – M4. Figure 3.19. Structures of Compounds Used for M2&4 Receptors Test. Figure 3.20. Secondary Binding Result – 5HT2B. Figure 3.21. Secondary Binding Result – 5HT6. xii Figure 3.22. Structures of Compounds Used for 5-HT Receptors Tests. Figure 3.23. Secondary Binding Result – Sigma 2. Figure 3.24. Structures of Compounds Used for Sigma 2 Receptor Tests. xiii Abbreviations AD = Alzheimer’s disease ADHD = attention deficit/hyperactivity disorder AIBN = Azobisisobutyronitrile AIDS = acquired immune deficiency syndrome AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ASD = autism spectrum disorder Aβ = amyloid β-peptides BBB = Blood-brain barrier BZD = benzodiazepine cAMP = cyclic adenosine monophosphate CCR5 = C-C chemokine receptor type 5 clogP = Calculated logP CNS = Central nervous system CT = computed tomography D1-5 = dopamine receptors 1-5 DALY = disability-adjusted life years xiv DCM = Dichloromethane DMF = Dimethylformamide DTG = ditolylguanidine EC80 = 80% effective concentration EEG = electroencephalogram FMR1