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GAEL) – Hybrids Design, Synthesis and Antitumor Properties of Glycosylated Antitumor Ether Lipid (GAEL) – Hybrids By Temilolu Idowu A thesis submitted to the Faculty of Graduate Studies of The University of Manitoba in partial fulfillment of the requirements of the degree of Master of Science Department of Chemistry University of Manitoba Winnipeg, Manitoba, Canada Copyright © 2015 by Temilolu Idowu To my cute little niece, Bliss Temitope Adedeji, that came just at the nick of time. ii ABSTRACT The development of resistance to apoptotic pathways by cancer cells is one of the great impediments to the successful use of chemotherapeutic agents. The development of resistance may be attributed to the role of cancer stem cells in the progression of this disease. One approach to combat drug resistance involves the use of drug combinations that impact multiple targets simultaneously. Although this is believed to be better at controlling complex disease systems, it has often proven to be of limited benefits in terms of overall therapeutic outcomes in cancer treatment. Glycosylated antitumor ether lipids (GAELs) are an emerging class of novel anticancer molecules that is being investigated as potential anticancer drugs. Interest in this class of drug is based on their ability to kill cancer stem cells as well as their non-apoptotic mechanism of action. This provides new opportunities to manipulate cell death in a therapeutic context, especially the renewed ability to kill apoptosis-resistant cancer cells. We therefore hypothesized that hybrid molecules that combine apoptosis-dependent and apoptosis-independent mode of actions in a single molecule may lead to better therapeutic outcomes. We also posited that the amphiphilic nature of GAELs could be modulated and fine-tuned to give a more potent analog. This dissertation describes the antitumor activities of different analogs of GAEL– chlorambucil hybrids and different triamino analogs. In all, eleven GAEL analogs were synthesized. Their activities, as well as that of reference compounds, were assessed against breast (JIMT1, MDA-MB-231, BT474), pancreas (MiaPaCa2) and prostate (DU145, PC3) cancer cell lines using the MTS assay. Our results reveal that the hybrid concept is a potential viable avenue to pursue as a therapeutic option especially when the other domain is carefully selected (Chapter 3). Moreover, the evidently more potent triamino analog not only corroborate the plausibility of a hybrid drug, it also revealed an important detail about the amphiphilic–cytotoxic relationships of GAELs (Chapter 4). iii ACKNOWLEDGEMENTS My heartfelt appreciation goes to my indefatigable supervisor, Dr. Frank Schweizer, for his unquantifiable support and understanding, and also for guiding my feet through the ‘wilderness’ of organic synthesis. His astuteness, inquisitiveness, resourcefulness and right amount of scientific skepticism have rightly shaped me in the pursuit of excellence. He is ever ready and willing to help whenever I run into troubled waters. Also to my co-supervisor, my committee member and our long-standing collaborator, Dr. Gilbert Arthur: his calmness, dexterity, and keen attention to details are unparalleled and ‘contagious’. The invaluable contributions of Dr. Pranati Samadder to the success of this work are also deeply appreciated. Many thanks to members of my examining committee: Drs. Jorg Stetefeld, Rebecca Davis and Gilbert Arthur, for your patience, constructive feedbacks and quick response whenever I beckon on you. It was a delight having you all in my committee. A big shout out to members of the ‘Schweizer Research Group’: Dr. Yaozu Xu, Dr. Fan Zhang, Dr. Bala Kishan Gorityala, Dr. Goutam Guchhait, Makanjuola Ogunsina, Xuan Yang, Ronald Domalaon and Yinfeng Lyu. Thanks for the friendly ambience, the oneness of purpose and for always providing shoulders to lean on. The camaraderie of the summer students (Lucas Vasas, Pavan Badogoo and Yaroslav Sanchak) also injected new enthusiasm into the laboratory. I salute you all. More importantly will I remain eternally grateful to my parents and siblings for always igniting and re-igniting the ‘can do’ spirit in me. My lovely sweetheart has also been very understanding and accommodating for as long as I have been away. Finally, all glory to the immortal, invisible and only wise God. Nothing compares to you. iv TABLE OF CONTENTS ABSTRACT ......................................................................................................................... iii ACKNOWLEDGEMENTS ............................................................................................... iv TABLE OF CONTENTS ..................................................................................................... v LIST OF TABLES ............................................................................................................. vii LIST OF FIGURES .......................................................................................................... viii LIST OF SCHEMES .......................................................................................................... ix LIST OF ABBREVIATIONS .............................................................................................. x CHAPTER ONE: INTRODUCTION AND BACKGROUND ......................................... 1 1 INTRODUCTION .......................................................................................................... 2 1.1 Management of Cancer .............................................................................................. 4 1.1.1 Shortcomings of current chemotherapeutic agents ............................................. 6 1.2 Antitumor Ether Lipids .............................................................................................. 7 1.3 Glycosylated Antitumor Ether Lipids ........................................................................ 9 1.3.1 Structure-Activity Relationships (SAR) ........................................................... 11 1.3.2 Challenges and Limitations of GAELs ............................................................. 14 1.4 Justification for the Study ........................................................................................ 15 1.4.1 The Hybrid Concept .......................................................................................... 16 1.4.2 Cancer Cell Death ............................................................................................. 19 1.4.3 Hypothesis......................................................................................................... 22 1.5 Measurement of Cytotoxicity (cell viability) ........................................................... 23 1.5.1 MTT/MTS Assay .............................................................................................. 24 1.5.2 LDH (lactate dehydrogenase)-based Assay ...................................................... 26 1.5.3 ATP-dependent Bioluminescence ..................................................................... 27 CHAPTER TWO ................................................................................................................ 29 2 THESIS OBJECTIVE .................................................................................................. 30 CHAPTER THREE: GAEL – CHLORAMBUCIL HYBRIDS ..................................... 32 3 ABSTRACT ................................................................................................................... 33 3.1 Introduction .............................................................................................................. 34 3.2 Results and Discussion ............................................................................................ 36 v 3.2.1 Chemistry .......................................................................................................... 36 3.2.2 Cytotoxicity....................................................................................................... 40 3.3 Conclusions .............................................................................................................. 44 CHAPTER FOUR: TRICATIONIC GAELs ................................................................... 45 4 ABSTRACT ................................................................................................................... 46 4.1 Introduction .............................................................................................................. 47 4.2 Results and Discussion ............................................................................................ 51 4.2.1 Chemistry .......................................................................................................... 51 4.2.2 Cytotoxicity....................................................................................................... 55 4.3 Conclusions .............................................................................................................. 60 CHAPTER FIVE: CONCLUSIONS ................................................................................. 61 5 CONCLUSIONS AND OUTLOOK ............................................................................ 62 5.1 Conclusions .............................................................................................................. 62 5.2 Outlook .................................................................................................................... 63 CHAPTER SIX: EXPERIMENTAL SECTION ............................................................
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