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Nitric Oxide- and Nitroxyl-Releasing Diazeniumdiolates in Pharmaceutical and Biomedical Research Applications Nitric Oxide- and Nitroxyl-Releasing Diazeniumdiolates in Pharmaceutical and Biomedical Research Applications Item Type Electronic Dissertation; text Authors Salmon, Debra J. 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 24/09/2021 19:54:40 Link to Item http://hdl.handle.net/10150/145389 NITRIC OXIDE- AND NITROXYL-RELEASING DIAZENIUMDIOLATES IN PHARMACEUTICAL AND BIOMEDICAL RESEARCH APPLICATIONS by Debra Jane Susan Salmon _____________________ A Dissertation Submitted to the Faculty of the DEPARTMENT OF CHEMISTRY & 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 2011 2 THE UNIVERSITY OF ARIZONA GRADUATE COLLEGE As members of the Dissertation Committee, we certify that we have read the dissertation prepared by Debra J. Salmon entitled "Nitric Oxide- and Nitroxyl-Releasing Diazeniumdiolates in Pharmaceutical and Biomedical Research Applications" and recommend that it be accepted as fulfilling the dissertation requirement for the Degree of Doctor of Philosophy _______________________________________________________________________ Date: 2/8/2011 Dr. Katrina Miranda _______________________________________________________________________ Date: 2/8/2011 Dr. John Enemark _______________________________________________________________________ Date: 2/8/2011 Dr. Indraneel Ghosh _______________________________________________________________________ Date: 2/8/2011 Dr. Richard Glass _______________________________________________________________________ Date: 2/8/2011 Dr. Dennis Lichtenberger 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: 2/8/2011 Dissertation Director: Dr. Katrina 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 head of the major department of the Dean of the Graduate College when in his or her judgment the proposed use of the material is in the interests of scholarship. In all other instances, however, permission must be obtained from the author. SIGNED: Debra J. Salmon 4 ACKNOWLEDGMENTS This dissertation would not have been possible without the constant support and guidance of Dr. Katrina M. Miranda. She has given me many opportunities to learn scientific techniques in a variety of locations and has taught me that I can push myself further than I thought possible. I would like to express my gratitude to Dr. Hartmut Jaeschke (University of Kansas Medical Center), Dr. David A. Wink (National Cancer Institute/National Institutes of Health), and Dr. Larry K. Keefer (NCI-Frederick) for opening up their labs to me and being excellent collaborators. My committee members (Drs. John H. Enemark, Indraneel Ghosh, Richard S. Glass, Dennis L. Lichtenberger) have provided invaluable scientific insight and discussion. I would also like to acknowledge all my past and present colleagues in the Miranda group for their helpful suggestions and friendship along the way. In particular Dr. Claudia L. Torres de Holding and Dr. Patricia G.Z. Benini were great friends and mentors in the lab. I am indebted to all members of the University of Arizona Department of Chemistry & Biochemistry for inspiring and teaching me along the way. Finally, I am grateful to my family and friends, whose support has also made this journey possible. 5 DEDICATION I would like to dedicate this work to my parents, Bonnie and Garrett Salmon. You are the first chemists in my life and have always been my biggest supporters. 6 TABLE OF CONTENTS LIST OF TABLES ........................................................................................................12 LIST OF FIGURES ......................................................................................................13 LIST OF EQUATIONS................................................................................................21 LIST OF SCHEMES ....................................................................................................23 LIST OF ABBREVIATIONS ......................................................................................26 ABSTRACT...................................................................................................................29 1 INTRODUCTION......................................................................................................31 1.1 The Chemical Biology of HNO ..........................................................................31 1.1.1 Introduction to nitrogen oxides.......................................................................31 1.1.2 Chemistry of HNO...........................................................................................32 1.2 Donors of HNO....................................................................................................39 1.2.1 Angeli’s salt ...................................................................................................40 1.2.2 Piloty’s acid ...................................................................................................41 1.2.3 N-hydroxyurea and related compounds.........................................................41 1.2.4 Cyanamide .....................................................................................................42 1.2.5 Diazeniumdiolates...........................................................................................45 1.2.6 Metal-nitroxyl complexes................................................................................48 1.3 Detection of HNO................................................................................................49 1.3.1 Spectrophotometric methods.........................................................................49 1.3.2 Fluorescence detection .................................................................................51 1.3.3 Electrochemical methods..............................................................................53 1.3.4 Chemiluminescence method..........................................................................53 1.3.5 HPLC method................................................................................................54 1.3.6 Gas chromatography .....................................................................................56 1.4 Pharmacological utility of HNO ........................................................................56 1.4.1 Cardiovascular system....................................................................................57 7 TABLE OF CONTENTS-continued 1.4.2 Cancer..................................................................................................................58 1.5 Summary..............................................................................................................59 2 COMPARISON OF IONIC AND PRODRUG NONOATES.................................60 2.1 Introduction.........................................................................................................60 2.2 Experimental .......................................................................................................62 2.2.1 Chemicals.......................................................................................................62 2.2.2 Synthesis of IPA/NO.......................................................................................62 2.2.3 Synthesis of AcOM-IPA/NO...........................................................................63 2.2.4 Instrumentation..............................................................................................64 2.2.5 Determination of rate constants.....................................................................65 2.2.6 Electrochemical measurements .....................................................................66 2.2.7 Reductive nitrosylation of metMb ..................................................................66 2.3 Results ..................................................................................................................68 2.3.1 Rate constants of Angeli’s salt and IPA/NO decomposition..........................69 2.3.2 Dependence of donor profile on pH...............................................................71 2.3.3 Determination of NONOate pKa values.........................................................75 2.3.4 Dissociation Mechanisms of Angeli’s salt and IPA/NO ................................76 2.3.5 Donor Chemistry of Angeli’s salt and IPA/NO..............................................80
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