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Multivalently Presented Carbohydrates Can Be MULTIVALENTLY PRESENTED CARBOHYDRATES CAN BE USED AS DRUG DELIVERY VEHICLES AND TO STUDY PROTEIN CARBOHYDRATE INTERACTIONS by Harrison Wesley VanKoten A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry MONTANA STATE UNIVERSTIY Bozeman, Montana July 2018 COPYRIGHT by Harrison Wesley VanKoten 2018 All Rights Reserved ii This was for me, in honor of my parents and family. iii ACKNOWLEDGEMENTS Most of all I would like to thank my father. I would not be here without your encouragement and commitment to my success. You inspired my work ethic, you supported me though the lows of life, and you are a constant source of support. Mercedes, I appreciate the fact that we can have extremely honest conversations. I know we always joke about how mom and dad were less strict on me, but really, I learned from your mistakes. Thanks for making them so I didn’t have to. To the rest of my family, thank you for putting up with my shenanigans. You were always there for me. I have a wonderful family and that I am eternally grateful for. Aaron and Kayla, you were always there at the right time to help me, probably more than you are aware of. I would also like to thank my advisor Mary. Thanks for believing in me and showing me how having a passion for science, a never-ending quest to learn, and a relentless drive for excellence can be so rewarding. I would also like to thank my spiritual advisor, T. N. Jones. Jon, Sam, and Sarah, I could not ask for better people to share an office with. To me our office became a safe space to vent about life’s (research) problems. I can’t tell you how important that is to me. I appreciate you. Finally, I want to thank my mother. Thank you for allowing me to pursue my interests and encouraging my education. You and dad built the foundation of the person I have become, and I am forever grateful. I miss you more than I can put into words. iv TABLE OF CONTENTS 1.INTRODUCTION TO CARBOHYDRATES, GALECTINS, AND HOW MULTIVALENCY CAN BE USED TO STUDY BIOLOGICAL SYSTEMS ............................................................................................................. 1 1.1.Overview of Multivalently Presented Carbohydrates Using Dendritic Scaffold for the Study of Protein-Carbohydrate interactions ...................................................................................................... 3 1.2.Galectins .......................................................................................................... 7 1.2.1.Galectin-3 .................................................................................................9 1.2.2.Galectin Research in this Thesis .......................................................... 10 1.2.3.Matrix Metalloproteinases ..................................................................... 11 1.3.Using Synthetically Conjugated Carbohydrates on a PAMAM Scaffold as Nanotherapies and to Study Protein Carbohydrate Interactions .................................................................................................... 14 1.3.1.RNAi induced gene suppression to study protein carbohydrate interactions ...................................................................... 19 1.4.Summary of Chapter One ............................................................................. 21 2.SYNTHESIS AND EVALUATION OF THE BIOLOGICAL ACTIVITY OF HIGHLY CATIONIC DENDRIMER ANTIBIOTIC ......................................... 24 2.1.Introduction .................................................................................................... 24 2.2.Results and Discussion ................................................................................. 29 2.2.1.Synthesis of C16-DABCO Dendrimers. ................................................. 29 2.2.2.Determination of the Minimum Inhibitory Concentrations. ................... 31 2.2.3.Hemolysis and Mammalian Cell Toxicity Assays. ................................ 35 2.2.4.Biofilm Disruption and Formation Studies. ........................................... 39 2.2.5.Multistep Resistance Selections Studies.............................................. 42 2.3.Conclusion ..................................................................................................... 45 2.4.Materials and Methods .................................................................................. 47 3.PROBING THE LEC-1 AND LEC-10 OXIDATIVE STRESS PATHWAY IN CAENORHABDITIS ELEGANS USING GALβ1-4FUC DENDRIMERS .................................................................................................... 54 3.1.Introduction .................................................................................................... 54 3.2.Results ........................................................................................................... 58 3.2.1.Synthesis of Galβ1-4Fuc. ..................................................................... 58 3.2.2.Reduction of Galectin Expression Increases Susceptibility to Oxidative Stress ................................................................................ 60 3.2.3.Fluorescent microscopy studies show localization of dendrimers ............................................................................................. 67 v TABLE OF CONTENTS CONTINUED 3.3.Future Directions ........................................................................................... 71 3.4.Conclusion ..................................................................................................... 73 3.5.Materials and Methods .................................................................................. 74 4.USING GLYCODENDRIMER WITH CLEAVABLE MMP SUBSTRATE TO STUDY DRUG RELEASE ..................................................... 83 4.1.Introduction .................................................................................................... 83 4.2.Dendrimers as Drug Delivery Vehicles ......................................................... 87 4.3.Results and Discussion ................................................................................. 88 4.3.1.Fluorescence Assay to Monitor Substrate Cleavage ........................... 90 4.4.Conclusion ..................................................................................................... 93 4.5.Materials and Methods .................................................................................. 94 4.5.1.General Methods .................................................................................. 94 5.APPENDICES .................................................................................................... 99 5.1.APPENDIX A ............................................................................................... 100 5.2.APPENDIX B ............................................................................................... 102 6.REFERENCES CITED ..................................................................................... 140 vi LIST OF TABLES Table Page 1. Minimum Inhibitory Concentrations (MICs) for Dendrimer 1 and Monomer 2. ................................................................................................. 33 2. Minimum hemolysis concentrations. .......................................................... 36 3. Minimum Inhibitory Concentrations (MICs) for Dendrimer 1 and Monomer 2. ............................................................................................... 138 vii LIST OF FIGURES Figure Page 1. Examples of Multivalent binding. ................................................................. 4 2. The subfamilies of galectins. ........................................................................ 8 3. Crystal structure overlay of the catalytic domain of MMP2 and MMP9.......................................................................................................... 12 4. An amine terminated generation 2, G(2) PAMAM dendrimer. .................. 18 5. Highly cationic dendrimer antibiotic 1. ....................................................... 27 6. Biofilm disruption studies. .......................................................................... 40 7. Resistance selection studies. ..................................................................... 43 8. Oxidative stress assay with galectin knockouts. ....................................... 60 9. Oxidative stress assays with dendrimers. ................................................. 63 10. Survival plots of C. elegans knockouts. ..................................................... 64 11. Fluorescent microscopy images of L4440(RNAi) worms with fluorescent Galβ1-4Fuc functionalized G2 dendrimer 10. ........................ 69 12. Fluorescent microscopy images of wildtype C. elegans treated with fluorescent Galβ1-4Fuc G2 dendrimers. ............................................ 70 13. Fluorescence intensity of MMP7 substrates incubated with A549 cells. .................................................................................................. 90 14. Fluorescence intensity of MMP2/9 substrates incubated with A549 cells. .................................................................................................. 91 15. 1H NMR of compound 8a. ........................................................................ 103 16. 13C NMR of 8a. ......................................................................................... 104 17. 1H NMR of product 8b. ............................................................................
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