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Alkyne-Nitrone Cycloadditions for Functionalizing Cell Surface Proteins

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Alkyne-Nitrone Cycloadditions for Functionalizing Cell Surface Proteins Alkyne-Nitrone Cycloadditions for Functionalizing Cell Surface Proteins by Craig McKay Thesis Submitted to the Faculty of Graduate and Postdoctoral Studies In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Candidate Supervisor Craig McKay Dr. John Paul Pezacki Ottawa-Carleton Chemistry Institute Faculty of Science University of Ottawa © Craig McKay, Ottawa, Canada, 2012 Alkyne-Nitrone Cycloadditions for Functionalizing Cell Surface Proteins by Craig McKay Submitted to the Faculty of Graduate and Postdoctoral Studies On July 31, 2012 in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy In Organic Chemistry Abstract Over the past decade, bioorthogonal chemistry has emerged as powerful tools used for tracking biomolecules within living systems. Despite the vast number of organic transformations in the literature, only select few reactions meet the stringent requirements of bioorthogonality. There is increasing demands to develop biocompatible reactions that display high specificity and exquisitely fast kinetics under physiological conditions. With the goal of increasing reaction rates as a means for reducing the concentrations of labelling reagents used for bioconjugation, we have developed metal-catalyzed and metal-free alkyne- nitrone cycloadditions as alternatives to azide-alkyne cycloadditions and demonstrate their applications for imaging cell surface proteins. The copper(I)-catalyzed alkyne-nitrone cycloaddition, also known as the Kinugasa reaction, is typically conducted with a Cu(I) catalyst in the absence of air. We have developed highly efficient micelle promoted multicomponent Kinugasa reactions in aqueous media to make the reaction faster and more efficient. Despite good product yields, the slow kinetics, limited substrate scope and competing side-reaction pathways precludes its practical applicability for biological labelling. We have designed and synthesized β-lactam alkyne probes obtained from these reactions for activity-based protein profiling of the activities of membrane proteins. Additionally, we report that alkyne tethered β-lactams serve as surface enhanced Raman spectroscopy (SERS) reporters bound to silver nanoparticles, and demonstrated that alkyne bound silver nanoparticles can be used for SERS imaging cell surface proteins. The strain-promoted alkyne-nitrone cycloaddition (SPANC) was also explored as a rapid alternative bioorthogonal reaction. We found that the reaction proceeded in high yield within aqueous media, and displayed rate enhancements that were 1-2 orders of magnitude faster than analogous reactions involving azides. The scope and kinetics of SPANC was evaluated in model reactions of various nitrones (acyclic and cyclic) with cyclooctynes, with the purpose of identifying stable nitrones that displayed intrinsically faster kinetics than azides in strain-promoted cycloadditions with cyclooctynes. Cyclic nitrones displayed good stability and exceptionally fast reactivity in these reactions. The SPANC reaction exhibited high selectivity in the presence of biological nucleophilic amino acid side chains and the presence of biological media did not adversely affect the reaction. We have utilized SPANC for highly specific labelling of proteins in vitro and for imaging ligand-receptor interactions on the surfaces of live cancer cells. The high selectivity, fast reaction rate, and aqueous compatibility of SPANC makes the reaction suitable for a variety of in vivo biological imaging applications. ii Acknowledgements Graduate studies at the University of Ottawa, and particularly research in the Pezacki Lab at the National Research Council of Canada, have been a truly wonderful experience. First and foremost, I would like to express my sincere gratitude to my supervisor, Dr. John Paul Pezacki, for his skilled guidance and mentorship. John, you have maintained the fine balance of promoting independence while providing thoughtful direction. I admire your interest in investigating problems at the interface of chemistry and biology. Thank you for providing me with many opportunities to attend scientific conferences and for your influence on my scientific development. Also, thank you for hosting and always providing excellent food and swimming at the annual “Pezacki Lab Classic.” I would also like to acknowledge my committee members for taking time out of their busy schedules to be on my committee and for reading my thesis. Much of the work presented in this thesis is the result of collaborations with colleagues in the Pezacki lab. To all the lab members that I have had the honour of working with, thank you for your friendship and making the lab a fun place to work. I thank my chemistry lab comrades with whom I worked for the majority of my graduate studies: Mr. Marc Legault, Dr. Joseph Moran, Dr. David Kennedy, Mrs. Mariya Chigrinova, Dr. Robert Faragher and Mr. Yiming Qian. I would also like to thank Dr. Selena Sagan, Mr. Ragunath Singaravelu and Mr. Rodney Lyn for sharing their knowledge of HCV biology and CARS microscopy. I am also thankful to past lab mates, particularly Dr. Bojana Rakic, Dr. Rajmohan Poondra, Dr. Stutti Srivastava and Dr. Jyoti Nandi for helping me with my first experiments in the synthetic chemistry lab. I am thankful to Mr. Donald M. Leek for assistance with NMR, and Mrs. Malgosia Daroszewska for her assistance with MS and RP- HPLC method development. To all the other graduate and undergraduates students, technicians and post-docs I have had the pleasure of working with, thank you for providing an exceptional environment in which to learn and grow. My family has been tremendously supportive and encouraging throughout the course of my graduate studies and education in general. I thank my parents, Gordon and Lynn McKay, and my sister, Megan, for their support and encouragement, and most importantly for believing in my potential, even at times when I had difficulty believing in myself. I will never be able to thank them for everything that they have done for me and I will always be grateful. I would also like to express acknowledgments to my beautiful and loving wife, Jenny, whom I met at the National Research Council in Ottawa at the beginning of my graduate studies. She has been extremely patient and encouraging throughout. She is an amazing person, an excellent scientist and I am lucky to have her in my life. iii Table of Contents Abstract ................................................................................................................................... ii Acknowledgements ................................................................................................................ iii List of Abbreviations ............................................................................................................. vi List of Figures ........................................................................................................................ ix List of Schemes ...................................................................................................................... xi List of Tables ....................................................................................................................... xiii Chapter 1 : Click Chemistry and Bioorthogonal Reactions ............................................... 1 Introduction .......................................................................................................................... 2 Oxime/Hydrazone Ligations ............................................................................................ 7 Staudinger Ligations ........................................................................................................ 9 Copper(I)-Catalyzed Azide-Alkyne Cycloadditions ...................................................... 10 Strain-Promoted Azide-Alkyne Cycloadditions ............................................................. 12 Cycloadditions of Azides with Strained Alkenes ........................................................... 18 Cycloadditions of Nitrile-Oxides with Strained Alkenes. .............................................. 19 Tetrazole-Alkene Cycloaddition Reactions ................................................................... 20 Tetrazine-Based Inverse-Electron Demand Diels-Alder Reactions ............................... 22 Olefin Metathesis on Proteins ........................................................................................ 25 Palladium Catalyzed Cross-Coupling Reactions ............................................................ 26 Quadricyclane Ligations ................................................................................................ 28 Conclusions ........................................................................................................................ 29 Thesis Outlook ................................................................................................................... 30 References .......................................................................................................................... 32 Chapter 2 : Studies of Micelle-Promoted Kinugasa Reactions in Aqueous Media ........ 38 Introduction ........................................................................................................................ 39 Hypothesis .......................................................................................................................... 47 Results and Discussion ......................................................................................................
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