EFFICACY OF A SERIES OF ORGANOMETALLIC POLYMERS AS ANTI-CANCER AND ANTIVIRAL AGENTS by LINDSEY CAITLIN MILLER DISSERTATION Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at The University of Texas at Arlington August 2017 Arlington, Texas Supervising Committee: Michael Roner, Supervising Professor Thomas Chrzanowski Woo-Suk Chang Paul Chippindale Shawn Christensen ABSTRACT EFFICACY OF A SERIES OF ORGANOMETALLIC POLYMERS AS ANTI-CANCER AND ANTIVIRAL AGENTS Lindsey Caitlin Miller, Ph.D. The University of Texas at Arlington, 2017 Supervising Professor: Michael Roner Organometallic compounds, particularly organotin compounds, have been known to possess biological activity for over 80 years. A variety of these compounds have demonstrated antimicrobial, anti- cancer, and antiviral activities. With the discovery of the anti-cancer ability of cisplatin, the most widely used chemotherapeutic agent, the interest in the potential capabilities of metal-containing compounds increased substantially. Since then, several metal-containing compounds have been evaluated for their microbiological activity, and our laboratory focuses specifically on organometallic polymers. Our compounds are composed of a metal, especially tin, which acts as the Lewis acid, while the Lewis base in our compounds is provided by a variety of biologically active compounds. Through condensation reactions pioneered by Dr. Charles Carraher (Florida Atlantic University), we have been able to test a variety of organometallic compounds against an array of bacteria, cancer cell lines, and most recently, viruses. The present study summarizes the previous work demonstrating the anti-cancer ability of organometallic compounds, followed by the most recent studies involving the assessment of their antiviral activity. The viruses in this study include vaccinia virus, a double-stranded DNA virus, and Zika virus, a single stranded (+) RNA virus. In terms of anti-cancer ability, the polymers derived from group IV metallocenes show the most promise for future chemotherapeutic use. The polymers with the greatest potential for antiviral use against vaccinia virus are the group III compounds, which are compounds derived from various organotins and 3-amino-1,2-4 triazole. Three compounds have shown promise against Zika virus: compounds KB5, KB8, and FM1. The most promising group of polymers against two ii strains of Zika virus (501 and 502) are group II compounds, which are derived from various organotins and camphoric acid. iii Copyright by Lindsey Caitlin Miller 2017 iv ACKNOWLEDGEMENTS I would first like to acknowledge my principal investigator, mentor, and friend, Dr. Michael Roner, without whom none of this research would have been accomplished. Dr. Roner, it has been five years since you took me under your wing. During those five years, I have worked on several research projects. Despite the failures I encountered, your faith in my aptitude as a scientist has never once wavered. Your willingness to help me with the smallest tasks has not gone unnoticed, and I could never thank you enough for all that you have done for me. You have shown me incredible patience and invaluable guidance over years of fighting with my cell cultures. I would also like to thank my current undergraduate assistants, Alison Egert and Caitlynn Reeves. You have been invaluable to me, both in my data collection and in acting as my laboratory emotional support systems when my research would not seem to cooperate. For all the times you came into lab with me on Saturday mornings, thank you. August 07, 2017 v DEDICATION I dedicate this work to my grandfather, Jidu, and to my parents, Sean and Cheryl. Thank you for supporting me in every endeavor imaginable for 29 years. I would never have accomplished obtaining a doctoral degree without, among other things, your emotional and financial guidance throughout the years. This is for you. vi TABLE OF CONTENTS Acknowledgements .............................................................................................................. v Dedication ............................................................................................................................. vi Abstract ................................................................................................................................ ii List of Figures ..................................................................................................................... viii List of Tables ........................................................................................................................ix Chapter 1 Organotins and Their Polymers ........................................................................... 1 Chapter 2 Organotins as Anti-Cancer Agents Literature Review ......................................... 16 Chapter 3 Simple Diol Polyethers Publication ...................................................................... 24 Chapter 4 Organotins and Prostate Cancer Publication ..................................................... 44 Chapter 5 Organotins and Breast Cancer Publication .......................................................... 89 Chapter 6 Thiamine Polymers Publication ............................................................................ 126 Chapter 7 Thiodiglycolic Acid Polymers Publication ............................................................. 161 Chapter 8 Dipicolinic Acid Polymers Publication .................................................................. 205 Chapter 9 Organotin/CHA Polymers Publication .................................................................. 230 Chapter 10 Metallocene/CHA Polymers Publication ............................................................ 268 Chapter 11 Titanocene/PEG Polymers Publication .............................................................. 285 Chapter 12 3,5-PA Polymers Publication .............................................................................. 321 Chapter 13 Group VA/Camphoric Acid Polymers Publication .............................................. 346 Chapter 14 Organotins as Antiviral Agents ........................................................................... 373 Chapter 15 Conclusions .................................................................................................... 387 vii LIST OF FIGURES Chapter 1 Figure 1 Group I Polymer Structure .................................................................................... 10 Figure 2 Group II Polymer Structure ..................................................................................... 10 Figure 3 Group III Polymer Structure .................................................................................. 11 Figure 4 Group IV Polymer Structure .................................................................................. 11 Figure 5 Group V Polymer Structure ................................................................................... 11 Figure 6 Group IV Polymer Structure .................................................................................. 12 Figure 7 Group VIIA Polymer Structure .............................................................................. 12 Figure 8 Group VIIB Polymer Structure .............................................................................. 12 Figure 9 Group VIIC Polymer Structure .............................................................................. 13 Figure 10 Group VIID Polymer Structure ........................................................................... 13 Chapter 14 Figure 1 Vaccinia Plaque Reduction Assay Control Plate ................................................. 384 Figure 2 Vaccinia Plaque Reduction Assay Compound Test Plate ...................................... 385 Figure 3 Zika Virus Control Non-Infected Vero Cells ............................................................ 385 Figure 4 Zika-Infected Vero Cells ...................................................................................... 386 Figure 5 Zika-Infected Vero Cells with Compound AC4 ................................................... 387 viii LIST OF TABLES Chapter 1 Table 1 Group I Compounds: Polyamines Derived from Various 4,6-Diaminopyrimidines .. 7 Table 2 Group II Compounds: Diorganotins + Camphoric Acid ........................................... 7 Table 3 Group III Compounds: Diorganotins + 3-amino-1,2-4 triazole ................................ 7 Table 4 Group IV Compounds: Triphenyl-containing compounds + camphoric acid .......... 8 Table 5 Group V Compounds: Organometallic compounds + dicumarol ............................ 8 Table 6 Group VI Compounds: Organotin dihalides + alpha-4-CHA ................................... 8 Table 7 Group VIIA Compounds: Titanocene + PEGs ........................................................ 9 Table 8 Group VIIB Compounds: Zirconocene + PEGs ...................................................... 9 Table 9 Group VIIC Compounds: Hafnocene + PEGs......................................................... 9 Table 10 Group VIID Compounds: Diphenyl/dibutyltin + PEGs ......................................... 10 Chapter 14 Table 1 Group II Compounds Vaccinia PRA Results: Diorganotins + Camphoric Acid .... 381 Table 2 Group III Compounds Vaccinia Virus: 3-AT Derivatives ....................................... 381 Table 3 Group IV Compounds Vaccinia Plaque Reduction Assay Results ....................... 382 Table 4 Group V Compounds Vaccinia PRA