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Synthesis of Antimycobacterial Agents That Harness Mycothiol and Cysteine Conjugate Β-Lyase Metabolic Pathways

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Synthesis of Antimycobacterial Agents That Harness Mycothiol and Cysteine Conjugate Β-Lyase Metabolic Pathways Synthesis of Antimycobacterial Agents that Harness Mycothiol and Cysteine conjugate β-lyase Metabolic Pathways by Scott W. Riordan A thesis submitted to Victoria University of Wellington in fulfilment of the requirements for the degree of Master of Biomedical Science Victoria University of Wellington 2015 Abstract Mycobacterium tuberculosis kills approximately two million people each year and is second only to HIV/AIDs in terms of death from infectious disease. The most pertinent problem in regards to Mycobacterium tuberculosis today is the increasing prevalence of drug resistant strains. Thus, there is a great need for the development of new drugs with novel targets. This thesis aimed to address this problem by synthesizing a compound that could exploit the mycothiol detoxification pathway, unique to Mycobacterium, in order to cause cell death, through the release of a harmful halothioketene. Mycothiol Detoxifaction β-Lyase Pathway Halothioketene Synthetic Target The research described herein involved the successful synthesis of the desired mycothiol analogue, along with three other related compounds. The target compounds were synthesised via protection of N-acetyl glucosamine, followed by thioglycosidation with cyclohexane thiol. Subsequent deprotection and coupling to Boc protected S- trichlorovinyl cysteine provided access to the synthetic target and its β-anomer, as well as their Boc protected precursors. The original synthetic target demonstrated weak antimycobacterial activity against Mycobacterium smegmatis and an encouraging sub 100 µM MIC against Mycobacterium bovis derived Bacillus Calmette–Guérin. Unexpectedly the beta anomer of the synthetic target also displayed antimycobacterial activity against Bacillus Calmette–Guérin (MIC 125 - 250 µM). All compounds proved to be active against HL60 cells (16-114 µM). ii Whilst further work is required to improve efficacy, the work presented here demonstrates the potential of these compounds as leads for the generation of new antimycobacterial agents. iii Acknowledgements There are many people I would like to thank. Firstly, Paul, I could not have asked for a better supervisor. Throughout the course of my studies your office door was always open and you were always happy to discuss results, no matter how busy you might have been. While your knowledge in both biochemistry and organic chemistry made these talks invaluable. I would also like to take the time to thank my co-supervisor Joanne. Your positive outlook, eye for detail and vast organic chemistry knowledge was a huge help. To all the people who occupied 205 east end during the course of my thesis, thanks for the all the good times and helpful discussions that took place. Specifically regarding my thesis, it was fantastic to have my synthesised compounds tested. So thanks to Jessica, Hilary and Nathaniel for making this possible. I would like to thank my family for all the moral support over the years and for showing an interest in my study, despite the fact my answers probably did not make much sense. For their financial support, I would like to thank my nana Alison and granddad Tony, it was a great help. Aunty Carolyn, uncle Niven and Robbie, thanks for letting me stay your at your place while I finished of my thesis, it saved me a lot of hassle, towards to the end of my thesis. Finally, to my parents, to you I owe my biggest gratitude, for without your support and encouragement none of this would be possible. iv Table of Contents Abstract ......................................................................................................................................... ii Acknowledgements....................................................................................................................... iv List of Figures ...............................................................................................................................viii List of Schemes ............................................................................................................................. ix List of Tables .................................................................................................................................. x List of Abbreviations ..................................................................................................................... xi 1. Introduction ............................................................................................................................... 1 1.1 Mycobacterium tuberculosis ................................................................................................ 1 1.1.1 Epidemiology ................................................................................................................. 1 1.1.2 Current Treatment ......................................................................................................... 2 1.1.2.1 Vaccines.................................................................................................................. 2 1.1.2.2 Antibiotics............................................................................................................... 2 1.1.3 Drug Resistance ............................................................................................................. 3 1.1.3.1 Phenotypic Resistance ............................................................................................ 3 1.1.3.2 Genetic Resistance .................................................................................................. 4 1.1.4 Future Treatment Targets .............................................................................................. 4 1.2 Mycothiol ............................................................................................................................. 6 1.2.1 Mycothiol Structure ....................................................................................................... 6 1.2.2 Role of Mycothiol .......................................................................................................... 6 1.2.3 Targeting Mycothiol....................................................................................................... 7 1.2.3.1 Mycothiol Biosynthesis ........................................................................................... 7 1.2.3.2 Mycothiol Disulfide Reductase ................................................................................ 8 1.2.3.3 Mycothiol S-Conjugate Amidase.............................................................................. 9 1.3 Halogenated Alkenes .......................................................................................................... 10 1.3.1 Halogenanted Alkene Toxicity ...................................................................................... 10 1.3.1.1 Halogenated Alkenes and their Uses ..................................................................... 10 1.3.1.2 Discovery of Toxicity ............................................................................................. 10 1.3.1.3 Animal studies and Human studies on Toxicity and Carcinogenicity....................... 11 1.3.2 Halogenated Alkene Metabolism ................................................................................. 12 v 1.3.2.1 Detoxicification Routes ......................................................................................... 12 1.3.2.2 Glutathione Metabolism ....................................................................................... 12 1.3.3 Cysteine Conjugate β-Lyases ....................................................................................... 13 1.3.3.1 Distribution and Discovery .................................................................................... 13 1.3.3.2 Cysteine S-Conjugate Metabolism by β-Lyases ...................................................... 14 1.3.4 Halothioalkene Toxicity ............................................................................................... 14 1.4 Mycothiol Induced Toxicity ................................................................................................. 15 1.4.1 Mycothiol and Glutathione Pathway ............................................................................ 15 1.4.2 Subverting the Mycothiol Pathway .............................................................................. 16 1.4.3 Proposed Mechanism for Conjugated Mycothiol Analogue .......................................... 16 1.5 Structure Design ................................................................................................................. 17 1.5.1 Cysteine N-Acetylation and Hydroxyl Removal ............................................................. 17 1.5.2 Cysteine-S-Conjugate Selection .................................................................................... 18 1.5.2.1 Haloalkene Selection ............................................................................................. 18 1.5.2.2 Fluorescent Tag Selection ..................................................................................... 18 1.6 Chemical Synthesis of Mycothiol ........................................................................................ 19 1.6.1 Past Syntheses of Mycothiol ........................................................................................ 19 1.6.2 Knapp et al. (2002) Synthesis of a Mycothiol Analogue ................................................ 20 1.6.3 Synthetic Plan for this Study .......................................................................................
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