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Synthesis and Mass Spectrometry of Bisconjugate Phase II Steroids

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Synthesis and Mass Spectrometry of Bisconjugate Phase II Steroids Synthesis and Mass Spectrometry of Bisconjugate Phase II Steroids A thesis submitted for the degree of Master of Philosophy of The Australian National University Research School of Chemistry The Australian National University August 18 © Copyright by Andy Pranata, 2018 All rights reserved Author’s declaration I declare that the work reported in this thesis was done by the author between September 2016 and May 2018 at the Research School of Chemistry at the Australian National University under the supervision of Associate Professor Malcolm McLeod, or otherwise has been appropriately referenced to the original publications. This thesis has not been previously submitted for any degree at any university and does not exceed 60,000 words. Andy Pranata 23 August 2018 ii Acknowledgements First of all, I would like to thank my supervisor, Associate Professor Malcolm McLeod, for giving me a position in the group (with scholarship) after my Honours year, sharing his knowledge, and supporting me throughout the year. Thank you to Dr. Bradley Stevenson for guiding me on how to make the glucuronylsynthase enzyme. Also to Dr. Hideki Onagi for teaching me about LC-MS/MS and helping me to run the experiments. Many thanks to the previous and current members of the McLeod group. Especially Dr. Chris Waller and Dr. Paul Ma as previous members, who had experience in making steroid reference materials. The Honours trio, Patrick Yates, Christopher Fitzgerald, and Katelyn Wilson who were always there to share cakes and hummus. Thanks to Erin Westley for being an exceptional summer research student in the group. And many thanks to the rest of McLeod group for making my time in the lab very enjoyable. Thank you to all RSC staff (technical officers, mass spectrometry, stores, and admin). Last but not least, I would like to thank my parents and my brother for supporting me. I would not be able to go through this year without them. iii Abstract The work described in this thesis details the efforts towards the synthesis of steroid bisconjugate materials. Specifically, a library of ten steroid sulfate glucuronide and ten bisglucuronide reference materials were prepared. In addition, a study of their mass spectrometry (MS) behaviour was conducted, with the goal of using these reference materials to identify new urinary markers that can then be used in anti-doping or diagnostic applications. Two extra steroid bis(sulfates) were also synthesised as reference materials for prenatal diagnosis. Chapter 1 introduces steroids in general, their metabolism in mammalian systems, the strengths and limitations of the current steroid detection methods, and how they can be improved. Chapter 2 discusses the synthetic steps that were taken to produce the steroid sulfate glucuronides and bisglucuronides, including stable isotope labelled derivatives. This includes a discussion of the sulfation, reduction, and glucuronylation reactions. This chapter also explains the MS study of the reference materials that were synthesised, especially using tandem mass spectrometry (MS/MS). It also details an LC-MS method developed to identify new steroid markers in human urine and efforts to confirm their identities against the prepared materials. Chapter 3 discusses the synthetic steps that were taken to produce the steroid bis(sulfates) to be used as reference materials in prenatal diagnosis. Experimental procedures for the synthesis of these compounds are also presented. Chapter 4 concludes the work presented in this thesis followed by suggestions for future work in this field. iv Abbreviations AAS androgenic anabolic steroids ABP Athlete Biological Passport ATP adenosine triphosphate br broad CID collision induced dissociation CIL constant ion loss conv. conversion δ chemical shift d doublet DHEA dehydroepiandrosterone DMF N,N-dimethylformamide EA epiandrosterone E. coli Escherichia coli (epi)DHT (epi)dihydrotestosterone (epi)T (epi)testosterone eq. equivalent(s) ESI electrospray ionisation (mass spectrometry) GC-MS gas chromatography-mass spectrometry h hour(s) HRMS high-resolution mass spectrometry IR infrared J coupling constant (Hz) LC-MS liquid chromatography-mass spectrometry LRMS low-resolution mass spectrometry m multiplet MS mass spectrometry v MS/MS tandem mass spectrometry m/z mass-to-charge ratio NL neutral loss NMR nuclear magnetic resonance PaS Pseudomonas aeruginosa arylsulfatase PORD cytochrome P450 Oxido-Reductase Deficiency ppm parts per million q quartet Rf retention factor s singlet SIM single ion monitoring SLOS Smith-Lemli-Opitz Syndrome SO3·py sulfur trioxide-pyridine complex SPE solid phase extraction SRM selected reaction monitoring STSD Steroid Sulfatase Deficiency SULT(s) sulfotransferase(s) t triplet TLC thin layer chromatography TMS trimethylsilyl UDPGA uridine diphosphate glucuronic acid UGT(s) uridine 5’-diphosphoglucuronosyltransferase(s) UPLC-MS/MS ultra-performance liquid chromatography–tandem mass spectrometry v/v unit volume per unit volume (ratio) WADA World Anti-Doping Agency WAX weak anion exchange vi Steroid nomenclature In Figure i, the numbering of steroid core is shown as well as the numbering of the extra carbons from the conjugate groups 1. When both conjugate groups at the two ends of the steroid structure contain carbons, numbering continues from the conjugate at the lowest numbered steroid carbon. Figure i shows four possible doubly conjugated steroid metabolites with their names shown. The naming system used in this thesis is not fully systematic and always the steroid name (following the IUPAC rules) followed by the conjugate position (if required) and name. It is important to note that compounds that have two glucuronide units are called bisglucuronides where the two glucuronic acid units are attached at two different sites. This is not to be confused with diglucuronide conjugates that have two glucuronic acid units connected at a single site 2,3. Figure i. Examples of bisconjugate steroids with numbering of steroid core and conjugates According to their structures, the steroids presented in this thesis can be classed as one of four types: androstane, estrane, pregnane, and cholane (Figure ii). Figure ii. Different structure of steroids vii Contents Author’s declaration ............................................................................................................. ii Acknowledgements ............................................................................................................. iii Abstract ............................................................................................................................... iv Abbreviations ....................................................................................................................... v Steroid nomenclature ......................................................................................................... vii Contents ........................................................................................................................... viii Chapter 1 – Introduction ...................................................................................................... 1 1.1. Steroids ..................................................................................................................... 1 1.2. Steroid metabolism .................................................................................................... 1 1.3. Steroid detection (LC-MS vs GC-MS) ....................................................................... 2 1.4. Importance of bisconjugate steroid metabolites ........................................................ 3 1.5. Previous syntheses of steroid bisglucuronides and sulfate glucuronides .................. 5 Chapter 2 – Steroid Bisglucuronides and Sulfate Glucuronides .......................................... 8 2.1. Foreword ................................................................................................................... 8 2.2. Synthesis of Steroid Bisglucuronide and Sulfate Glucuronide Reference Materials: Unearthing Neglected Treasures of Steroid Metabolism ................................................ 14 Chapter 3 – Steroid Bis(sulfates) ..................................................................................... 105 3.1. Foreword ............................................................................................................... 105 3.2. Steroid sulfation pathways targeted by disulfates determination. Application to prenatal diagnosis. ....................................................................................................... 107 3.3. Experimental section ............................................................................................. 143 3.3.1. Materials ......................................................................................................... 143 3.3.2. Instruments ..................................................................................................... 143 3.3.3. 5α-Pregnane-3β,20S-diol bis(sulfate), ammonium salt ................................... 144 3.3.4. 21-Hydroxypregnenolone ............................................................................... 144 3.3.5. 21-Hydroxypregnenolone bis(sulfate), ammonium salt ................................... 145 Chapter 4 – Conclusions and Future Work ...................................................................... 146 References .....................................................................................................................
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