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The Therapeutic Targeting of Folate Receptor Alpha Positive Tumors Wayne State University Wayne State University Dissertations 1-1-2015 The Therapeutic Targeting Of Folate Receptor Alpha Positive Tumors Via Folate Receptor Selective Novel 5- And 6- Substituted Pyrrolo [2,3-D]pyrimidine Antifolates" Shermaine Kimberly Mitchell-Ryan Wayne State University, Follow this and additional works at: http://digitalcommons.wayne.edu/oa_dissertations Part of the Molecular Biology Commons, Oncology Commons, and the Pharmacology Commons Recommended Citation Mitchell-Ryan, Shermaine Kimberly, "The Therapeutic Targeting Of Folate Receptor Alpha Positive Tumors Via Folate Receptor Selective Novel 5- And 6- Substituted Pyrrolo [2,3-D]pyrimidine Antifolates"" (2015). Wayne State University Dissertations. Paper 1155. 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. THE THERAPEUTIC TARGETING OF FOLATE RECPTOR ALPHA POSITIVE TUMORS VIA FOLATE RECEPTOR-SELECTIVE NOVEL 5-AND 6- SUBSTITUTED PYRROLO [2,3-D] PYRIMIDINE ANTIFOLATES by SHERMAINE KIMBERLY MITCHELL-RYAN DISSERTATION Submitted to the Graduate School of Wayne State University, Detroit, Michigan In partial fulfilment of the requirements for the degree of DOCTOR OF PHILOSOPHY 2015 Major: CANCER BIOLOGY Approved By: ________________________________________ Advisor Date ________________________________________ ________________________________________ ________________________________________ ________________________________________ DEDICATION This dissertation is dedicated to Seamus Isaiah Ryan, my sun (son), my world and my very reason to press forward and claim every reward life has to offer. My sojourn through this process would not have been possible without the love, support and encouragement of my husband, Paul Seamus Ryan. Thank you for your steadfast devotion, patience and understanding. You have been my guiding light, offering important insight in some of my darkest moments. You are the quintessential professional and the lessons that you have imparted upon me about maintaining my integrity and professionalism in every situation are some of greatest lessons learned. My strong sense of self, determination and integrity were instilled by the late Sherman Mitchell (father) and Agnes Bryant (grandmother). You taught me to have faith and confidence in myself and my abilities, which in turn helped me to gauge my self-worth. This self-esteem has served as yard stick to help me measure up to the person I envision myself to be and to accept nothing less while being intolerant of disrespect and unjust injury to my person. My quest to have an impact on the world was strengthened by my life-long mentor, Dr. Frazier O’Leary. You are the mentor I want to be. I hope to influence the lives of my students the way you have and continue to influence mine. Finally, just as I have stood firmly on the shoulder of giants, the trials I blaze are meant to uncover a path for every girl of color who has dreams that drift them to careers in science. Do not allow discouraging words to drown your curiosity. You and you alone are the ruler of your destiny. ii ACKNOWLEDGEMENTS I like to acknowledge and thank both past and present members of the Matherly lab for your instruction, support and laughs throughout my stay. I would like to give special thanks to Dr. Mark Stout, Dr. Eric Hales, Dr. Zhangjun Hou and Dr. Lisa Polin (and staff) for being instrumental in the completion, training and analysis of many of the experiments performed in this body of work. Your rigorous examination of questions and pursuit of quality data have taught me to think as a scientist and to produce and present work that I can proudly defend. I would like to acknowledge Dr. Larry Matherly for the use of space and tools to explore the questions offered in this dissertation. Thank you to Dr. Aleem Gangjee, our collaborating medicinal chemistry for sharing some of the most fascinating compounds. You made the chemistry of your compounds palatable and easy to process. The National Institute of Health Ruth L. Kirschstein National Research Service Awards for Individual Predoctoral Fellowships to Promote Diversity in Health-Related Research (F31), The Cancer Biology Graduate Program’s T32 training grant, and the Wayne State Graduate Program’s Dean’s Diversity fellowship provided financial support for my graduate education. I would also like to extend my gratitude to my surrogate mentor, Dr. Stanley Terlecky, who has always been a huge source of encouragement and support. You have played an instrumental role in my growth as a scientist from my start as first year student to the present. Finally a word of thanks to of the brilliant women scientists I encountered during my time at Wayne State (Dr. Malathy Shekhar, Dr. Karin List, Dr. Ellen Tisdale, Dr. Julie Boerner, Dr. Izabela Podgroski) who were excellent role models and instructors. iii TABLE OF CONTENTS Dedication ...................................................................................................................................... ii Acknowledgements ....................................................................................................................... iii List of Tables ................................................................................................................................ vi List of Figures .............................................................................................................................. vii Abbreviations ................................................................................................................................ ix Chapter 1: Introduction: Folates in human health.......................................................................... 1 1.1 The identification and isolation of folate ..................................................................... 1 1.2 Folate biology and chemistry ....................................................................................... 3 1.3 Folate tissue absorption.............................................................................................. 21 1.4 Folate based targeted therapy..................................................................................... 43 1.5 Ovarian cancer ........................................................................................................... 57 Chapter 2: Discovery of 5-Substituted Pyrrolo[2,3-d]pyrimidine Antifolates as Dual Acting Inhibitors of Glycinamide Ribonucleotide Formyltransferase and 5- Aminoimidazole-4- Carboxamide Ribonucleotide Formyltransferase in de novo Purine Nucleotide Biosynthesis: Implications of inhibiting 5-aminoimidazole-4- carboxamide ribonucleotide formyltransferase to AMPK activation and anti-tumor activity.................................................................................................................................... 69 2.1 Introduction ................................................................................................................ 69 2.2 Biological evaluation ................................................................................................. 75 2.3 Discussion .................................................................................................................. 97 2.4 Materials and methods ............................................................................................. 100 Chapter 3: Discussion ................................................................................................................ 107 3.1 Targeting the AMPK/mTOR pathway ..................................................................... 108 3.2 Targeting AICARFTase ........................................................................................... 110 References .................................................................................................................................. 114 Abstract ...................................................................................................................................... 152 iv Autobiographical Statement....................................................................................................... 154 v LIST OF TABLES Table 1.1: A commonly used FRα positive cell line model with commonly used ovarian cell line models ................................................................................................................ 64 Table 2.1: IC50s (in nM) for 5- and 6-substituted pyrrrolo[2,3-d]pyrimidine antifolates and classical antifolates in RFC-, PCFT-, and FR-expressing cell lines .................... 81-82 vi LIST OF FIGURES Figure 1.1: The reduction of folic acid .......................................................................................... 5 Figure 1.2: Enzymatically active folate metabolites ...................................................................... 6 Figure 1.3: De novo purine biosynthesis...................................................................................... 16 Figure 1.4: The purine salvage pathway and cellular products ................................................... 18 Figure 1.5: The compartmentalization of folate metabolism ....................................................... 20 Figure 1.6: Predicted topology map of human reduced folate carrier (hRFC) ............................ 25 Figure 1.7: Homology model and predicted membrane topology for hPCFT
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