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Synthesis and Pharmacological Evaluation of Nitrogen Oxide Releasing Prodrugs Item Type text; Electronic Dissertation Authors Bharadwaj, Gaurav Publisher The University of Arizona. Rights Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. Download date 04/10/2021 11:39:05 Link to Item http://hdl.handle.net/10150/301748 SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF NITROGEN OXIDE RELEASING PRODRUGS by Gaurav Bharadwaj _____________________ A Dissertation Submitted to the Faculty of the DEPARTMENT OF CHEMISTRY AND BIOCHEMISTRY In Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY WITH A MAJOR IN CHEMISTRY In the Graduate College THE UNIVERSITY OF ARIZONA 2013 2 THE UNIVERSITY OF ARIZONA GRADUATE COLLEGE As members of the Dissertation Committee, we certify that we have read the dissertation prepared by Gaurav Bharadwaj entitled " SYNTHESIS AND PHARMCOLOGICAL EVALUATION OF NITROGEN OXIDE RELEASING PRODRUGS " and recommend that it be accepted as fulfilling the dissertation requirement for the Degree of Doctor of Philosophy _______________________________________________________________________ Date: 03/18/2013 Dr. Katrina M. Miranda _______________________________________________________________________ Date: 03/18/2013 Dr. F. Ann Walker _______________________________________________________________________ Date: 03/18/2013 Dr. Richard Glass _______________________________________________________________________ Date: 03/18/2013 Dr. Hamish Christie Final approval and acceptance of this dissertation is contingent upon the candidate’s submission of the final copies of the dissertation to the Graduate College. I hereby certify that I have read this dissertation prepared under my direction and recommend that it be accepted as fulfilling the dissertation requirement. ________________________________________________ Date: 07/30/13 Dissertation Director: Dr. Katrina M. Miranda 3 STATEMENT BY AUTHOR This dissertation has been submitted in partial fulfillment of requirements for an advanced degree at the University of Arizona and is deposited in the University Library to be made available to borrowers under rules of the Library. Brief quotations from this dissertation are allowable without special permission, provided that accurate acknowledgment of source is made. Requests for permission for extended quotation from or reproduction of this manuscript in whole or in part may be granted by the author. SIGNED: Gaurav Bharadwaj 4 ACKNOWLEDGEMENTS It is my privilege to acknowledge the people who have been constant source of support and guidance though out my research work. First of all, I would like to express my indebtedness to my advisor Dr. Katrina Miranda for her inspiring and scholarly guidance, valuable suggestions, and constant support throughout my time at The University of Arizona work. She gave me complete freedom to explore new area and was a constant source of support during ups and downs in accomplishing those undertakings. I would also like to sincerely thank my committee members namely Dr. Walker, Dr. Glass and Dr. Christie for spending their valuable time and their constructive suggestions at various stages of the work that enabled me to improve upon the quality of the thesis. I would also thank faculty members of the Department of Chemistry and Biochemistry for their courses, which prepared me to understand the basics that were very useful during my research work. I would like to thank Dr. Debashree Basudhar, who started the NONO-NSAID project and I had the opportunity to work with her and get to know her. Presently she is my lovely wife, who has always believed in me and is a constant source of support. I would also like to express my sincere gratitude to present and past members of the Miranda research group at University of Arizona. They were not only a source of inspiration but also made working in the lab fun. I would specially like to thank Patricia Benini, who started the cyclic amine NONOate project. Also I would like to thank all the undergrads (Cyf, Michelle, Yannon and Kavya) with whom I got the chance to work and without their contribution, this work would not have been possible. Finally, I would like to thank my parents for motivating me to try for higher noble goals and render the best effort to achieve the same without being afraid of failure. Their sacrifice, patience and inspiration made me work harder. My brothers and my sister-in- law have always been a constant source of inspiration and support. 5 DEDICATION To my parents, my wife, brothers and sister-in-law, who have been a great source of inspiration and always supported me through good and bad times. 6 TABLE OF CONTENTS LIST OF FIGURES ............................................................................................................... 9 LIST OF SCHEMES ........................................................................................................... 14 LIST OF TABLES…………………………………………………………………………16 ABSTRACT ......................................................................................................................... 17 1 INTRODUCTION ....................................................................................................... 19 1.1. Nitric oxide ............................................................................................................. 19 1.2. Chemical biology of NO ......................................................................................... 22 1.3. Donors of NO .......................................................................................................... 24 1.3.1. Organic nitrates ........................................................................................... 24 1.3.2. Metal nitrosyl .............................................................................................. 26 1.3.3. S-Nitrosothiols (RSNO) .............................................................................. 29 1.3.4. Diazeniumdiolates....................................................................................... 30 1.4. Nitroxyl ................................................................................................................... 34 1.4.1. Donors of HNO ........................................................................................... 34 1.4.1.1. Angeli’s salt .......................................................................................... 35 1.4.1.2. Piloty’s acid .......................................................................................... 35 1.4.1.3 Acyl nitroso compounds ........................................................................ 36 1.4.1.4 Acyloxy nitroso Compounds ................................................................. 37 1.4.1.5 Primary amine based diazeniumdiolates ................................................ 38 1.5. Cancer and therapeutic potential of NO and HNO ................................................. 39 1.6. Breast cancer ........................................................................................................... 44 1.7. Tamoxifen ............................................................................................................... 46 1.8. Chlorambucil........................................................................................................... 47 1.9. NO-NSAIDs ............................................................................................................ 51 1.10. Conclusion ............................................................................................................ 52 Abbreviations ................................................................................................................. 54 7 2 NITROGEN OXIDE RELEASING DIAZEN-1-IUM-1,2-DIOLATE BASED ADDUCTS OF N-DESMETHYL-TAMOXIFEN ................................................... 55 2.1. Introduction ............................................................................................................. 55 2.2. Materials and methods ............................................................................................ 60 2.3. Results and discussions ........................................................................................... 66 2.3.1. Half-life of DEA/NO-AcOM and carbamate adducts ................................ 67 2.3.2. NO release profile of DEA/NO-AcOM ...................................................... 68 2.3.3. Chemiluminescence detection of NO/HNO from N-desmethytamoxifen adducts .................................................................................................................. 69 2.3.4. Intracellular release of NO/HNO ................................................................ 70 2.3.5. Cytotoxicity................................................................................................. 73 2.3.6. Attempted synthesis of new hybrid NO/HNO-N-desmethyltamoxifen adduct .................................................................................................................... 78 2.4. Conclusions ............................................................................................................. 82 Abbreviations ................................................................................................................
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