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Synthesis of Netilmicin and Apramycin Derivatives for the Rt Eatment of Multidrug- Resistant Infectious Diseases Amr Sayed Motawi Sonousi Wayne State University

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Synthesis of Netilmicin and Apramycin Derivatives for the Rt Eatment of Multidrug- Resistant Infectious Diseases Amr Sayed Motawi Sonousi Wayne State University Wayne State University Wayne State University Dissertations 1-1-2017 Synthesis Of Netilmicin And Apramycin Derivatives For The rT eatment Of Multidrug- Resistant Infectious Diseases Amr Sayed Motawi Sonousi Wayne State University, Follow this and additional works at: https://digitalcommons.wayne.edu/oa_dissertations Part of the Organic Chemistry Commons Recommended Citation Sonousi, Amr Sayed Motawi, "Synthesis Of Netilmicin And Apramycin Derivatives For The rT eatment Of Multidrug-Resistant Infectious Diseases" (2017). Wayne State University Dissertations. 1880. https://digitalcommons.wayne.edu/oa_dissertations/1880 This Open Access Dissertation is brought to you for free and open access by DigitalCommons@WayneState. It has been accepted for inclusion in Wayne State University Dissertations by an authorized administrator of DigitalCommons@WayneState. SYNTHESIS OF NETILMICIN AND APRAMYCIN DERIVATIVES FOR THE TREATMENT OF MULTIDRUG-RESISTANT INFECTIOUS DISEASES by AMR SONOUSI DISSERTATION Submitted to the Graduate School of Wayne State University, Detroit, Michigan in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY 2017 MAJOR: CHEMISTRY (Organic) Approved By: Advisor Date DEDICATION I dedicate my PhD work to my parents Sayed Sonousi and Hoda Fayed for nursing me with affection and love and for their dedicated partnership for success in my life. I also dedicate my work to my wife Tasnim Kandeel for her endless love and support for me throughout the process. ii ACKNOWLEDGEMENTS I would first like to express my utmost appreciation to my advisor, Professor David Crich, for his endless patience, brilliant guidance, continuous encouragement, and constant support during the past five years of my Ph.D. studies. His passion and dedication for science will always be my example to follow. Without the help and support from him, I would not have been able to finish this thesis. I would like to extend my appreciation to all of my committee members, Professors James Rigby, John SantaLucia and Steven Sucheck, for their precious time and for their suggestions made for my thesis dissertation. I also would like to thank our collaborators Professors Andrea Vasella, Erik C Böttger, Patrice Courvalin and Jochen Schacht for their contribution to my project My sincere thanks to my mentors who taught me during my first-year courses, especially Dr. Cha for the advanced organic reactions course as well as Drs Guo, Kodanko, Stockdill, Ahn and Hendrickson for the other organic and bio-organic courses. My profound gratitude goes to my present and past lab mates. Dr. Takayuki Kato, Dr. Takayuki Furukawa, Dr. Suresh Dharuman, and Dr. Takahiko Matsushita gave me much advice on my research. They were always willing to share their ideas with me in long discussions. I also thank Dr. Mandhapati for his help teaching me laboratory techniques and helping me familiarize myself with the lab in my first year; Philip, with whom I enjoyed working with on the same bench, and Dr. Buda, Dr. Popik, Peng, Harsha, Jessica, Girish, Bibek, Sandeep, Xiaoxiao, Guanyu, Mike, Mohamed, Philemon, and Jonathan for their timely help in the lab. Finally, I would like to thank the helpful staff in the chemistry department, as well as my supportive friends and family. iii TABLE OF CONTENTS Dedication ....................................................................................................................................... ii Acknowledgements ........................................................................................................................ iii Table of Contents ........................................................................................................................... iv List of Tables ............................................................................................................................... viii List of Figures ................................................................................................................................ ix List of Schemes ............................................................................................................................. xii List of Abbreviations ................................................................................................................... xiv Chapter 1. Introduction ................................................................................................................... 1 1.1. Background and significance ............................................................................................... 1 1.2. Structural features and classifications .................................................................................. 3 1.3. Mechanism of action of aminoglycosides ............................................................................ 5 1.3.1. AGA uptake ............................................................................................................. 5 1.3.2. Protein synthesis and AGA binding to the ribosomes ............................................. 6 1.4. Aminoglycoside resistance and toxicity ............................................................................ 11 1.4.1. Aminoglycoside resistance .................................................................................... 11 1.4.1.1. Reduction of aminoglycoside internal concentration ................................. 12 1.4.1.2. Ribosomal binding site modifications ........................................................ 13 1.4.1.3. Aminoglycoside modifying enzymes (AMEs) ........................................... 13 iv 1.4.2. Adverse effects of aminoglycosides ...................................................................... 16 1.4.2.1. Nephrotoxicity ............................................................................................ 17 1.4.2.2. Ototoxicity .................................................................................................. 18 1.5. Recent advances ................................................................................................................. 21 1.6. Overall goals ...................................................................................................................... 23 Chapter 2. Investigations in the 4,6-Class of AGAs ..................................................................... 24 2.1. Mode of binding of netilmicin to the bacterial ribosomal A-site....................................... 24 2.2. Synthesis of netilmicin ....................................................................................................... 25 2.3. Modifications of netilmicin................................................................................................ 26 2.4. Rational .............................................................................................................................. 29 2.5. Chemistry ........................................................................................................................... 29 2.5.1. Triazenes as a selective protecting group for secondary amines ........................... 29 2.5.2. Aryl triazenes ........................................................................................................ 30 2.5.3. Examples of selective protection ........................................................................... 33 2.5.4. Application to aminoglycosides ............................................................................ 35 2.5.5. Synthesis of netilmicin derivatives ........................................................................ 37 2.5.6. Synthesis of plazomicin ......................................................................................... 41 2.6. Biological Evaluation......................................................................................................... 44 2.7. Conclusion ......................................................................................................................... 48 Chapter 3. Development of Apramycin Derivatives with Modification at the 5-Position and Examination of their Antiribosomal and Antibacterial Activity................................................... 50 v 3.1. Mode of binding of apramycin to the bacterial ribosomal A-site ...................................... 50 3.2. Modifications of apramycin ............................................................................................... 51 3.2.1. Modifications at the 5- and 6-positions of apramycin ........................................... 52 3.2.2. Modifications at the N1,N2',N7',N4''-positions of apramycin ............................... 55 3.2.3. Modifications at the 6''-position of apramycin ...................................................... 58 3.2.4. Modifications at the N7’-Me and 6’-positions of apramycin ................................ 59 3.3. Rationale ............................................................................................................................ 60 3.4. Synthesis of apramycin derivatives ................................................................................... 63 3.4.1. Synthesis of a key apramycin intermediate ........................................................... 63 3.4.2. Synthesis of 5-O--ribofuranosyl apramycin, 5-O--paromobiosyl apramycin and 5-O--[3-O-(2-aminoethyl) ribofuranosyl] apramycin ......................................................... 64 3.4.3 Synthesis of 5-O--[3-O-(2-hydroxyethyl) ribofuranosyl] apramycin .................. 67 3.4.4.
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