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Application of the Sandmeyer Reaction Towards Synthesis of Selective Anderson 1 Application of the Sandmeyer Reaction Towards Synthesis of Selective Toll-like Receptor 7 & 8 Antagonists Rachel J. Anderson Undergraduate Thesis March 27th, 2018 University of Colorado Boulder Thesis Advisor: Hang Hubert Yin, Ph.D.: Department of Chemistry & Biochemistry Committee Members: Xuedong Liu, Ph.D.: Department of Chemistry & Biochemistry Jeffrey Cameron, Ph.D.: Department of Chemistry & Biochemistry Karolin Luger, Ph.D.: Department of Chemistry & Biochemistry Pamela Harvey, Ph.D.: Molecular, Cellular & Developmental Biology Anderson 2 ACKNOWLEDGEMENTS I would like to begin by thanking Professor Hubert Yin and my lab mates in the Yin lab for putting up with my antics over the past two years and providing a great place to learn. This project would not have been possible without the extensive support and guidance of my direct mentor, Dr. Rosaura Padilla-Salinas, who has invested untold hours into my success. I would like to specifically thank Josh Kamps, Shafer Soars, and Dr. Adam Csakai for feedback, advice, and moral support. I would also like to thank my thesis committee: Xuedong Liu, Jeffrey Cameron, Karolin Luger, and Pamela Harvey for their patience and assistance. Finally, I am grateful for financial support provided by the Undergraduate Research Opportunities Program (UROP) at the University of Colorado, Boulder which made eating possible. Anderson 3 TABLE OF CONTENTS 1. Abstract ....................................................................................................................................... 4 2. Introduction ................................................................................................................................ 4 2-1. Overview of the immune system ......................................................................................... 4 2-2. Toll-like receptors ................................................................................................................ 5 Historical context .................................................................................................................... 5 Function .................................................................................................................................. 6 Structure and signaling ........................................................................................................... 7 Role in chronic inflammation & autoimmunity ...................................................................... 8 Summary and project justification ........................................................................................ 10 3. Structure-activity relationship studies ...................................................................................... 11 3-1. Introduction ....................................................................................................................... 11 Previous work ....................................................................................................................... 11 The Sandmeyer reaction ....................................................................................................... 12 Amide synthesis reactions .................................................................................................... 15 Summary of biological assays ............................................................................................... 17 3-2. Modifications of ring A ....................................................................................................... 17 3-3. Modifications of ring B ....................................................................................................... 23 3-4. Modifications of ring C ....................................................................................................... 25 3-5. Modifications of amide linker ............................................................................................ 26 4. Discussion and future directions .............................................................................................. 30 5. References ................................................................................................................................ 31 6. Supporting Information ............................................................................................................ 35 6-1. Biological methods ............................................................................................................. 35 6-2. Chemical methods ............................................................................................................. 36 6-3. Reaction Protocols ............................................................................................................. 37 6-4. NMR Spectra ...................................................................................................................... 69 Anderson 4 1. ABSTRACT Toll-like receptors (TLRs) are an important part of the innate immune system responsible for detecting signs of microbial invasion and cell damage and initiating the immune response. Overactivation of TLRs, presumably by inappropriate detection of endogenous ligands, has been linked to chronic inflammation and autoimmunity. Current therapeutics are broad-spectrum and inhibit the overall function of the immune system. In this work, a library of dual-TLR7/8 antagonists were prepared with the goal of engineering TLR7 specificity, then tested against HEK 293 cells expressing either TLR 7 or 8. An antagonist with IC50 0.22 ± 0.33 μM against TLR 8 and greater than 50 μM against TLR 7 is presented, which may find use as a therapeutic or chemical probe. While this demonstrates that engineering specificity is possible, further work is required to locate a TLR7-selective antagonist. 2. INTRODUCTION 2-1. Overview of the immune system The innate immune system is our first line of defense against microbial threats. Our protection begins with physical barriers such as skin and mucosal membranes. Once a threat breaches these barriers, it will rapidly proliferate unless dealt with. The innate immune system is non-specific and acts within hours to inhibit unchecked microbial growth, but often cannot fully clear an infection. Instead, it primes the adaptive immune system for a much stronger pathogen-specific response, which will both clear the infection and “remember” the pathogen in order to more rapidly eliminate the pathogen if it is re-encountered1. Anderson 5 2-2. Toll-like receptors TLRs are pattern recognition receptors which bind conserved motifs of pathogen- associated molecular patterns (PAMPs) commonly expressed by invading microbes, or damage- associated molecular patterns (DAMPs) indicative of damaged and dying cells. The 10 human TLRs are primarily expressed in antigen-presenting cells, such as macrophages, dendritic cells, B-cells, and some epithelial cells2. TLRs are localized to either the plasma membrane (TLRs 1/2/4/5/10) or to the endosome (TLRs 3/7/8/9)3, and are thus positioned to sample the exterior environment of the cell. Historical context Despite the important role of TLRs in immunity, the toll gene was first identified in Drosophila in 1980 for its role in embryonic development and it was not discovered until 1995 that toll played a second role in innate immunity4. By 1998, five toll homologues were known in humans, forming the human Toll-like receptor (hTLR or TLR) family4,5. At the time, it was unclear how the innate immune system functioned, especially considering that it must somehow communicate with the adaptive immune system. In the two decades since, extensive research has shown that although TLRs do function as a first line of defense, many other signaling pathways coexist with TLRs, such as the cGAS/STING pathway6, NOD-like receptors7, and RIG-like receptors8. Uniquely, the ligands of many TLRs can be of exogenous or endogenous origin, suggesting a role for inappropriately activated TLRs in autoimmunity. Anderson 6 Function Figure 1. Overview of Toll-like receptors and their associated signaling pathways9. TLRs localized to the plasma membrane primarily detect conserved bacterial and fungal motifs (Figure 1). In addition to directly activating an immune response, these TLRs also have been shown to upregulate pinocytosis10, presumably to promote a stronger immune response. TLRs 1, 2, and 6 recognize a variety of lipopeptides, glucans, and teichoic acids commonly found in microbial membranes and cell walls2 and may indiscriminately dimerize (for example, dimers Anderson 7 of TLR 1/2 and 2/6 are known). TLR4 recognizes lipopolysaccharide, a common component of Gram-negative bacterial cell walls3. Although endosomal TLRs most commonly detect viral motifs, they may also detect endogenous ligands and thus they are thought to play a role in autoimmunity. TLR3 binds long stretches (40 or more bases) of double-stranded RNA11, which often signals invasion by enveloped viruses which pass through the endosome during their reproductive cycle. TLR9 detects unmethylated CpG double-stranded DNA3. As eukaryotic CpG DNA is commonly methylated, this indicates that the DNA may be of non-eukaryotic origin (i.e. bacterial or mitochondrial). TLRs 7 and 8 recognize single-stranded RNA and RNA degradation products (monomers and small oligonucleotides such as UUG)12,13. RNA may enter the endosome from the exterior of the cell (through endocytosis) or from the interior of the cell through incorporation into autophagosomes14. The role of TLR10 is poorly understood.
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