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Cost-Effective Synthesis, Bioactivity and Cellular Uptake Study of Aminoglycosides with Antimicrobial and Connexin Hemichannel Inhibitory Activity

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Cost-Effective Synthesis, Bioactivity and Cellular Uptake Study of Aminoglycosides with Antimicrobial and Connexin Hemichannel Inhibitory Activity Utah State University DigitalCommons@USU All Graduate Theses and Dissertations Graduate Studies 12-2019 Cost-Effective Synthesis, Bioactivity and Cellular Uptake Study of Aminoglycosides with Antimicrobial and Connexin Hemichannel Inhibitory Activity Yagya P. Subedi Utah State University Follow this and additional works at: https://digitalcommons.usu.edu/etd Part of the Chemistry Commons Recommended Citation Subedi, Yagya P., "Cost-Effective Synthesis, Bioactivity and Cellular Uptake Study of Aminoglycosides with Antimicrobial and Connexin Hemichannel Inhibitory Activity" (2019). All Graduate Theses and Dissertations. 7699. https://digitalcommons.usu.edu/etd/7699 This Dissertation is brought to you for free and open access by the Graduate Studies at DigitalCommons@USU. It has been accepted for inclusion in All Graduate Theses and Dissertations by an authorized administrator of DigitalCommons@USU. For more information, please contact [email protected]. COST-EFFECTIVE SYNTHESIS, BIOACTIVITY AND CELLULAR UPTAKE STUDY OF AMINOGLYCOSIDES WITH ANTIMICROBIAL AND CONNEXIN HEMICHANNEL INHIBITORY ACTIVITY Yagya P. Subedi A dissertation submitted in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in Chemistry Approved: ______________________ ____________________ Cheng-Wei Tom Chang, Ph.D. Alvan C. Hengge, Ph.D. Major Professor Committee Member ______________________ ____________________ Joan M. Hevel, Ph.D. Liaohai Chen, Ph.D. Committee Member Committee Member ______________________ ____________________ David W. Britt, Ph.D. Richard S. Inouye, Ph.D. Committee Member Vice Provost for Graduate Studies UTAH STATE UNIVERSITY Logan, Utah 2019 ii Copyright © Yagya P. Subedi 2019 All Rights Reserved iii ABSTRACT Cost-effective synthesis, bioactivity and cellular uptake study of aminoglycosides with antimicrobial and connexin hemichannel inhibitory activity by Yagya P. Subedi, Doctor of Philosophy in Chemistry Utah State University, 2019 Major Professor: Dr. Cheng-Wei Tom Chang Department: Chemistry and Biochemistry More than a billion people suffer from fungal diseases, and these diseases cost billions of dollars worldwide each year. The emergence of a fungal strain resistance to the first-line drugs, azoles, makes the situation even worst. Amphiphilic kanamycin is a new class of compounds with wide-spectrum antifungal activity towards susceptible and azole resistance strains. The higher cost of production and instability at acidic or basic conditions were the limiting factors of these antifungal compounds. Libraries of new 6ʺ modified amphiphilic kanamycins were synthesized with nitrogen and sulfur as the connector atoms. The leads identified after the SAR study of the new compounds have excellent activity towards plant and fungal pathogens and can tolerate different pH conditions. The cost of production of the lead compounds is higher amid improved antifungal activity. A library 6ʹ modified of amphiphilic kanamycin was synthesized from the one-step modification of kanamycin to resolve the cost issue. The lead from the library of 6ʹ amphiphilic kanamycin has similar activity to the lead from 6ʺ compounds. iv The newly identified lead from the library of 6ʹ modified kanamycin can be synthesized on a large scale without a need for conventional silica gel column chromatography, and the cost of production is competitive to currently marketed antifungals. Newly synthesized amphiphilic aminoglycosides have fungal selective activity. Using the fluorescent analogs, the fluorescent imaging of fungi, bacteria, and human cells shows the discrimination in cellular uptake was the reason behind selectivity. These fluorescent aminoglycosides reported here, with a fluorophore at 6ʹ and 6ʺ, can be used to stain fungi selectively. So these fluorescent analogs also have the potential to be fungal detecting probes. Abnormal opening of Cx43 hemichannel is associated with various diseases such as neurodegenerative disease, heart diseases, etc. So the Cx43 selective inhibitor may be useful in the treatment of these diseases. In search of an inhibitor selective towards Cx43 hemichannel, newly synthesized 6ʹ and 6ʺ modified kanamycin with aryl substitution and some known compounds were screened for connexin hemichannels inhibitory activity. The lead identified from these compounds has selective inhibitory activity towards Cx43 hemichannel. (261 pages) v PUBLIC ABSTRACT Cost-effective synthesis, bioactivity and cellular uptake study of aminoglycosides with antimicrobial and connexin hemichannel inhibitory activity by Yagya P. Subedi Amphiphilic kanamycin is one of the promising class of compounds for the treatment of fungal infections in plants and animal. Factor that lead to the restricting of compounds for commercialization includes, the higher cost of production and poor stability of the compound. However, the new lead, identified from the synthesis and biological testing, can be synthesized on a large scale with a cost comparable to commercial antifungals. The newly reported lead is stable at the acidic and basic conditions. Additionally, this compound has an excellent activity towards Candida auris, a multidrug-resistant superbug. Heart disease is the leading cause of death in the United States most of which are caused by cardiac ischemia and arrhythmias. Abnormal opening of Cx43 hemichannel can damage the heart muscles and lead to these conditions. A compound which can selectively inhibit the opening of Cx43 hemichannel may pave the way to reducing the mortality rate of heart disease. A selective inhibitor towards Cx43 hemichannel is explored from the synthesis and biological testing of kanamycin derivatives. The synthesis of the new inhibitor is scalable and cost-effective. vi ACKNOWLEDGMENTS First and foremost, I would like to express my appreciations and thanks to my advisor Dr. Cheng-Wei Tom Chang; it was a great pleasure to be his graduate student. His guidance, motivation, and supports in the last four years transform me from a fluster researcher to a synthetic chemist. His kindness and humbleness are irreplaceable. I also would like to thank Dr. Liaohai Chen for allowing me to work under his supervision in the first two years of PhD and providing constructive comments as a committee member. I learned biology and analytical techniques while working in Dr. Chen’s lab. I am thankful to other committee members Dr. Alvan C. Hengee, Dr. Joan M. Hevel, and Dr. David W. Britt, for encouragement and guidance throughout the journey to doctorate. I heartily appreciate the invaluable comments and suggestions from all of you. A special thanks to Dr. Hengge for helping to establish a human cell culture lab from the departmental support. It would be hard to complete all of my projects without this lab. I am grateful to our collaborator Dr. Jon Y. Takemoto from the Biology department at Utah State University for teaching me the biology aspect of my antifungal projects and his generosity. I never get a feel Takemoto lab is not my primary research lab while using resources from his lab. Thank you, Dr. Takemoto, for letting me use all the lab resources. I am also grateful to Dr. Michelle Grilley from the Takemoto lab for helping in the antifungal assay, teaching biological assays and helping me with the grammatical correction in this dissertation. I also would like to thank Dr. Guillermo A. Altenberg and his lab members for performing the connexin inhibitory assay of the compounds. I am thankful to the undergraduate researchers Paul Roberts, Heath Montgomery, vii Joey Rapp, Bjorn Rodriguez, Noah Thackeray, Gavin Nichols, Jeffrey Wight, Xinrui Peng and summer interns David Kennedy, Aleksei Ananin, Greg Becker for their helping hand in my research. It was a wonderful experience working with you all. I am also thankful to graduate students of the lab, Dr. Jaya P. Shrestha, Dr. Madher N. Alfindee, Uddav Pandey, for maintaining a friendly environment in the lab and helping in my graduate work. I would like to thank Cindy Weatbrook, and Margaret Dobrowolska for their help in all the difficulties and providing an exciting environment in the chemistry and biochemistry department. Both of you, marvelous lady, will be in my memory forever. I am thankful to Chemistry and Biochemistry, Utah State University, for the opportunity to pursue PhD degree. I am indebted to my parents for continuous support, love, care, and seeing their success in my progress. Thank you, Buba and Mummy, for inspiration to see a big dream and teaching to achieve that through hard work. I am also grateful to my sister and brother for their love and care throughout student life. Finally, I would like to thank all the friends and relatives who have been around physically or emotionally. Yagya P. Subedi, 2019 viii CONTENTS Page ABSTRACT ……………………………………………………………………………. iii PUBLIC ABSTRACT …………………………………………………………………... v ACKNOWLEDGMENTS ………………………………….…………………………... vi LIST OF TABLES ………………………………………..………………………...…... ix LIST OF FIGURES ……………………………………..………………………………. x LIST OF SCHEMES …………………………………..……………………………... xvii LIST OF ABBREVIATIONS ………………………..……………………………… xviii CHAPTER 1. GENERAL INTRODUCTION ………………………………………………......... 1 2. SCALABLE AND COST-EFFECTIVE TOSYLATION-MEDIATED SYNTHESIS OF ANTIFUNGAL AND FUNGAL DIAGNOSTIC 6″-MODIFIED AMPHIPHILIC ANAMYCINS ……………………………….... 34 3. DEVELOPMENT OF FUNGAL SELECTIVE AMPHIPHILIC KANAMYCIN: COST-EFFECTIVE SYNTHESIS AND USE OF FLUORESCENT ANALOGS FOR MODE OF ACTION INVESTIGATION ……………………. 64 4. AMPHIPHILIC AMINOGLYCOSIDES AS SELECTIVE
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