Louisiana State University LSU Digital Commons LSU Doctoral Dissertations Graduate School 2011 Characterization of Triggerable Quinones for the Development of Enzyme-Responsive Liposomes Maria Fabiana Mendoza Louisiana State University and Agricultural and Mechanical College, [email protected] Follow this and additional works at: https://digitalcommons.lsu.edu/gradschool_dissertations Part of the Chemistry Commons Recommended Citation Mendoza, Maria Fabiana, "Characterization of Triggerable Quinones for the Development of Enzyme-Responsive Liposomes" (2011). LSU Doctoral Dissertations. 1173. https://digitalcommons.lsu.edu/gradschool_dissertations/1173 This Dissertation is brought to you for free and open access by the Graduate School at LSU Digital Commons. It has been accepted for inclusion in LSU Doctoral Dissertations by an authorized graduate school editor of LSU Digital Commons. For more information, please [email protected]. CHARACTERIZATION OF TRIGGERABLE QUINONES FOR THE DEVELOPMENT OF ENZYME-RESPONSIVE LIPOSOMES A Dissertation Submitted to the Graduate Faculty of the Louisiana State University and Agricultural and Mechanical College in partial fulfillment of the Requirements for the degree of Doctor of Philosophy In The Department of Chemistry by Maria Fabiana Mendoza B.S., Missouri Baptist University, 2005 May 2012 DEDICATION This dissertation is dedicated to my loving grandmother: Mabel Cerri Burgantis de Mendoza And to My Mom, Ibis Elizabeth Paris Bargas My Dad, Hector Eduardo Mendoza Cerri My Brother, Facundo Horacio Jesus Mendoza Paris My Brother, Jose Hector Mendoza Paris My Partner, Dayna Tatiana Pastorino Martinez ii ACKNOWLEDGMENTS I would like to thank my advisor, Dr. Robin L. McCarley, for his extraordinarily guidance and support through all these years in graduate school. I still remember my visit to LSU and how from the moment I interacted with his graduate students and met him I knew that I would like to be a part of his group. I feel so lucky in having an advisor who I admired as a scientist and as a person. He will be definitely missed and I will always be grateful to God for putting him in my life. To the McCarley research group, thank you for your support and friendship. It was the collection of people from different background and cultures that made this group very special. It has been a pleasure to work with each of you and I wish you all the best in life. To my committee members, Dr. Doug Gilman, Dr. Carol Taylor, and Dr. Grover Waldrop, I would like to thank you all for always having your door open for me. To my Dean’s representative, Dr. Jin-Woo Choi and his substitute Dr. Dorel Moldovan, thank you for being in my general exam and final examination, respectively. I would also like to give special thanks to my colleagues Nicole Carrier, Jennifer De Guzman, Jeremiah Forsythe, and Elisabeta Mitran and to the Post-doctoral fellows in the McCarley group, Sreelatha Balamurugan, Winston Ong, and Martin Loew for their scientific discussions and proofreading of my documents. Nikki, Jenny, Eli and Sreelatha thanks for your friendship and I hope that we can continue to remain in touch for the rest of our lives. I appreciate my dear friends, Nadya Braida, Leila Juan, Florencia Belo, Victoria Garcia, Andres Vidal-Gadea and Santiago Claramunt for being there when I needed someone to cheer me up or just to listen. As a foreign person in the United State it has not always been easy and having friends willing to share some time and a word of encouragement has been of great help. To my family, and to those that have known me since I was a little girl, thank you for helping me to mature and giving me strength to continue on this journey. Mom, dad, Facundo iii and Jose thank you for helping me become into the person that I am today. I want to give a very special thanks to the most wonderful person in this world, my grandmother Mabel Cerri, whose unconditional love is greater than my words can express. She is definitely my heart and soul. I would also especially like to thank my partner Taty, for being there for me at all times. You provided the peace that allowed me to focus on writing and to complete this process in a timely manner. You have taken care of me and everything else around me, I am so grateful to have you in my life. Lastly, I would like to give thanks to all of the other the people that helped me through my graduate career here at LSU and especially those in the Department of Chemistry. iv TABLE OF CONTENTS DEDICATION ................................................................................................................................ ii ACKNOWLEDGMENTS ............................................................................................................. iii LIST OF TABLES ....................................................................................................................... viii LIST OF FIGURES ....................................................................................................................... ix LIST OF SCHEMES.................................................................................................................... xiv LIST OF ABBREVIATIONS AND SYMBOLS ..........................................................................xv ABSTRACT ...................................................................................................................................xx CHAPTER 1. INTRODUCTION ....................................................................................................1 1.1 Research Goals and Aims ....................................................................................................1 1.2 Prodrugs Activated by Endogenous Oxidoreductase Enzymes Other Than NQO1 ...........4 1.2.1 Aldehyde Oxidase ....................................................................................................5 1.2.2 Amino Acid Oxidases ..............................................................................................5 1.2.3 NADPH-Cytochrome P450 Reductase ....................................................................6 1.2.4 Cytochrome P450s ...................................................................................................8 1.2.5 Tyrosinase ..............................................................................................................10 1.3 Enzyme-Activated Liposomes ..........................................................................................12 1.3.1 Elastase ..................................................................................................................12 1.3.2 Alkaline Phosphatase .............................................................................................13 1.3.3 Phospholipase C .....................................................................................................14 1.3.4 Phospholipase A2 (PLA2) ......................................................................................15 1.3.5 Matrix Metalloproteinase (MMP) ..........................................................................18 1.4 NAD(P)H:Quinone Oxidoreductase Type-1 (NQO1) ......................................................21 1.4.1 Origin, Types, Structure, Mechanism, Location and Over Expression .................21 1.4.2 Inhibitors of Human NQO1 ...................................................................................24 1.4.3 Bioreductive Drugs Activated by Human NQO1 ..................................................27 1.4.4 Prodrugs Presenting the Trimethyl-lock System Activated by Human NQO1 .....31 1.5 References ..........................................................................................................................32 CHAPTER 2. ELECTROCHEMICAL BEHAVIOR OF QUINONE DERIVATIVES POTENTIALLY USABLE FOR DRUG DELIVERY APPLICATIONS ....................................53 2.1 Introduction ........................................................................................................................53 2.2 Experimental Section .........................................................................................................55 2.2.1 Materials and Methods ...........................................................................................55 2.3 Results and Discussion .....................................................................................................56 2.3.1 Thermodynamic Parameters of Naked Quinones ..................................................56 2.3.2 Thermodynamic Parameters of Propionic Acid Quinones and QMe-ETA .............59 v 2.3.3 Propionic Acid Quinones and Their Cyclization Behavior ...................................65 2.4 Conclusions ........................................................................................................................67 2.5 References ..........................................................................................................................68 CHAPTER 3. TRIGGERABLE QUINONES ACTIVATED BY NAD(P)H:QUINONE OXIDOREDUCTASE TYPE-1 (HNQO1) FOR POTENTIAL DRUG DELIVERY APPLICATIONS ...........................................................................................................................72 3.1 Introduction ........................................................................................................................72 3.2 Experimental Section ........................................................................................................74 3.2.1 Materials ................................................................................................................74