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Protected Triazabutadienes in Chemical Biology

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Protected Triazabutadienes in Chemical Biology Protected Triazabutadienes in Chemical Biology Item Type text; Electronic Dissertation Authors Guzman, Lindsay Eileen Citation Guzman, Lindsay Eileen. (2021). Protected Triazabutadienes in Chemical Biology (Doctoral dissertation, University of Arizona, Tucson, USA). Publisher The University of Arizona. Rights Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction, presentation (such as public display or performance) of protected items is prohibited except with permission of the author. Download date 10/10/2021 17:58:48 Link to Item http://hdl.handle.net/10150/657769 PROTECTED TRIAZABUTADIENES IN CHEMICAL BIOLOGY by Lindsay E. Guzman Copyright © Lindsay E. Guzman 2021 A Dissertation Submitted to the Faculty of the DEPARTMENT OF CHEMISTRY AND BIOCHEMISTRY In Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY WITH A MAJOR IN CHEMISTRY In the Graduate College THE UNIVERSITY OF ARIZONA 2021 THE UNIVERSITY OF ARIZONA GRADUATE COLLEGE As members of the Disse1iation Committee, we certifythat we have read the disse1tation prepared by: Lindsay E. Guzman titled: Protected Triazabutadienes in Chemical Biology and recommend that it be accepted as fulfilling the disse1tation requirement for the Degree of Doctor of Philosophy. Date: Mar 2, 2021 John C Jewett Date: Mar 5, 2021 lndraneel Ghosh Date: Mar 4, 2021 Richard Glass Date: Mar 2, 2021 William R Montfort Date: Mar 2, 2021 Michael A Riehle Final approval and acceptance of this disse1tation is contingent upon the candidate's submission of the final copies of the disse1tation to the Graduate College. I hereby ce1tifythat I have read this dissertation prepared under my direction and recommend that it be accepted as fulfilling the dissertation requirement. Date: Mar 2, 2021 John C Jewett Chemistry and Biochemistry Acknowledgements I am so thankful for many people that have helped me. I did not complete this PhD by myself. Many people contributed along the way. I will try my best to name all of the people who helped me along the way. But inevitably I will leave someone out. I’d like to thank my PhD adviser, Dr. John Jewett. Dr. Jewett runs an inclusive and positive research program, in which students are motivated to work through positive mentorship. I’d like to thank my friend and mentor, Dr. Flora Kimani. Flora trained me how to be an organic chemist and taught me everything I know about triazabutadiene chemistry. I appreciate Flora’s patience in me as a mentee, as I was constantly asking her questions and following her around lab. I also want to thank Flora for her friendship and support. I would like to thank Garrett Davis for teaching me how to work with proteins and run gels. Garrett contributed early work in the mosquito project as well. I would like to thank undergraduate students Anjali Patel and Yannick Schreiber. Yannick and Anjali were excellent undergraduate researchers and were willing to work and think critically about science. I would like to thank Anjalee Wijetunge for synthesizing compounds and for her willingness to learn new biochemical techniques. I’d like to thank Natasha Cornejo for synthesizing the alkyne protected triazabutadiene. I would like to thank all previous and current members of the Jewett lab: Abigail Shepard, Holly Sofka, Danielle Johnson, Dr. Jie He, Dr. Bereketab Mehari, Dr. Mehrdad Shadmehr, Dr. Diana Knyazeva Dr. Stephanie Monson, Dr. Ali Ahad, Brandon Cornali, Christy McDevitt, Jean Laurent-Blanche, Sam Garn, Jason Ha, Maddie Morrow, Nevan Madrid, and Mohamed Hamie. I would like to thank Dr. Mike Riehle for teaching me about mosquitoes and training me on biological techniques. I would like to thank Jenet Soto-Schoumaker for hatching all the eggs and prepping mosquito larvae for me every week. I’d like to thank Riehle lab members Dr. Frank Ramberg, Dr. Jun Isoe, Dr. Neha Thakare, Dr. Chioma Origanje Oparah, Teresa Joy, Minhao Chen, and Brendan Riske. I’d like to thank the Marley Imaging facility and Patty Jansma. I’d like to thank my committee members Dr. Neel Ghosh, Dr. Bill Montfort, and Dr. Mike Riehle for challenging me and guidance over the years. I would like to thank Lori Boyd for being the best graduate coordinator possible. I would like to thank the CBC department, the BCP program, Graduate College and the Dr. Maria Teresa Velez fellowship for their support. I’d like to thank the NMR and mass spectrometry facilities. I’d also like to thank my friends and family for their continuous support. 3 Dedication This dissertation is dedicated to mi familia. 4 Table of Contents Abstract.......................................................................................................................................... 13 Chapter 1 Benzene diazonium ions and proteins ..................................................................... 14 1.1 Introduction ........................................................................................................................... 14 1.2 Naturally occurring BDz ions ................................................................................................ 15 1.3 Chemistry of BDz ions .......................................................................................................... 16 1.4 BDz ion reactivity with amino acids ...................................................................................... 18 Coupling reactions with histidine ............................................................................................ 18 Coupling reactions with tyrosine ............................................................................................. 19 Reactions with -amino groups and lysine ............................................................................. 20 Reactions with cysteine .......................................................................................................... 21 Reactions with tryptophan ...................................................................................................... 22 Reactivity with other biological moieties ................................................................................. 23 1.5 Amino acid selectivity ........................................................................................................... 23 1.6 Azoproteins ........................................................................................................................... 24 1.7 Summary and Outlook .......................................................................................................... 25 Chapter 2 Design, synthesis, and reactivity of protected triazabutadienes .......................... 26 2.1 Introduction ........................................................................................................................... 26 2.2 Triazabutadienes as triggered chemical probes for BDz ion generation ............................. 26 2.3 Attempts to protect the triazabutadiene ................................................................................ 28 2.4 Initial stability experiments with the protected triazabutadiene ............................................ 32 2.5 Deprotection mechanism of the carbamate protecting group .............................................. 33 2.6 Ethyl carbamate stability in various contexts ........................................................................ 40 5 2.7 Future Directions................................................................................................................... 41 2.8 Conclusion ............................................................................................................................ 41 Chapter 3 Design and synthesis of functionalized protected triazabutadienes .................... 42 3.1 Introduction ........................................................................................................................... 42 3.2 Design of the protected triazabutadiene chemical probe ..................................................... 43 3.3 Synthesis of the protected triazabutadiene chemical probe ................................................. 44 3.4 Issues with the synthesis of the biotinylated probe .............................................................. 48 3.5 Synthesis of the biotinylated probe using Cu-free click chemistry ....................................... 51 3.6 Synthesis of functionalized protected triazabutadienes using Cu-click chemistry in water..52 3.7 Future Directions................................................................................................................... 53 3.8 Conclusion ............................................................................................................................ 53 Chapter 4 Identifying drug targets for mosquito population control ...................................... 54 4.1 Introduction ........................................................................................................................... 54 4.2 Targeting adult mosquitoes for population control ............................................................... 56 4.3 Targeting mosquito larvae for population control ................................................................. 60 4.4 Identifying new drug targets by understanding the mosquito gut ......................................... 61 4.5 In vivo chemical modification of proteins in the alimentary canal........................................
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