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Orthogonality in Natural Products Workflows UC San Diego UC San Diego Electronic Theses and Dissertations Title Orthogonality in Natural Products Workflows Permalink https://escholarship.org/uc/item/6hm5k9rr Author Boudreau, Paul Davis Publication Date 2015 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California UNIVERSITY OF CALIFORNIA, SAN DIEGO Orthogonality in Natural Products Workflows A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Marine Biology by Paul Davis Boudreau Committee in charge: Professor William H. Gerwick, Chair Professor Lihini Aluwihare Professor Pieter C. Dorrestein Professor William Fenical Professor Amro Hamdoun Professor Bradley Moore 2015 Copyright Paul Davis Boudreau, 2015 All rights reserved. The dissertation of Paul Davis Boudreau is approved, and it is acceptable in quality and form for publication on microfilm and electronically: Chair University of California, San Diego 2015 iii DEDICATION No one finishes a Ph. D. alone, I am no exception to this rule. The long list of people to thank begins before I even started this endeavor, with my family who have always supported me, thanks Mom, Dad, and Eleanor. At MIT, I wouldn’t have graduated without Zak Fallows and Jessica McKellar, my undergraduate lab partners; or First East, my residence hall on East Campus, who are all, simply put, awesome. Professor Rick Danheiser gave me my first opportunity to join a research project, which certainly led to me pursuing a Ph. D. I also thank the graduate students in the Danheiser lab, Xiao-Yin Mak is a tremendous scientist and incredible mentor who I learned a great deal from; Cindy Crosswhite, Shaun Fontaine, and Julia Robinson put up with me for so long, it’s hard to believe their patience. Professor Bill Gerwick allowed me to earn my Ph. D. in his lab, and I must thank the other students who entered the lab with me, Sam Mascuch, Emily Mevers, and Emily Trentacoste. They are a great cohort to work with but also the best people I could have asked to slog through grad-school with. Bailey Miller is a great collaborator and comrade in arms. Other friends, mentors, classmates, and troublemakers to thank include Marcy Balunas, Matt Bertin, Kerri Dawn, Ed Esquenazi, Alan Foreman, Bill Jones, Cliff Kapono, Don Nguyen, Laura Sanchez, Mindi Summers, Kevin Tidgewell, and many others. I got where I am because of you all, your are my heroes. iv EPIGRAPH What do you mean by “Accept misfortune as the human condition”? Misfortune comes from having a body. Without a body, how could there be misfortune? —Lao Tzu (Translation by Gia-fu Feng and Jane English) v TABLE OF CONTENTS Signature Page..................................... iii Dedication........................................ iv Epigraph.........................................v Table of Contents.................................... vi List of Figures...................................... ix List of Tables...................................... xv Acknowledgements................................... xvi Vita........................................... xvii Abstract of the Dissertation............................... xix Chapter 1 Marine Natural Products Chemistry, a Grand Balancing Act......1 1.1 Abstract..............................1 1.2 Introduction............................2 1.3 Discussion.............................4 1.3.1 Feature-Guided Isolation.................7 1.3.2 Comparative Metabolomics...............8 1.3.3 Genomics.........................9 1.3.4 Chemical Ecology.................... 10 1.4 Conclusions............................ 12 Chapter 2 The Viequeamides, Cyclic Desipeptides from a Tropical Filamentous Cyanobacterial Strain.......................... 13 2.1 Abstract.............................. 13 2.2 Introduction............................ 14 2.3 Results and Discussion...................... 15 2.4 Experimental Section....................... 31 2.4.1 General Experimental Procedures............ 31 2.4.2 Collection and Identification of Cyanobacteria..... 32 2.4.3 Polymerase Chain Reaction (PCR) and Cloning..... 33 2.4.4 Phylogenetic Inferences.................. 33 2.4.5 Cytotoxicity Assay.................... 34 2.4.6 Extraction and Isolation................. 35 2.4.7 LC-HRMS Fragmentation Analysis of Viequeamides B-F (26-30)........................ 37 vi 2.4.8 Stereochemical Analysis of Viequeamide A (25) by Mar- fey’s Analysis and Chiral GCMS............. 37 2.4.9 Stereochemical Analysis of Viequeamide B (26) by Mar- fey’s Analysis and Chiral GCMS............. 40 2.5 Acknowledgments........................ 42 Chapter 3 Difficulties in the Dereplication Workflow, the Need for Orthogonal Workflows................................ 43 3.1 Abstract.............................. 43 3.2 Introduction............................ 44 3.3 Results and Discussion...................... 47 3.3.1 MALDI-Phyloproteomics................ 47 3.3.2 Molecular Networking.................. 51 3.4 Conclusions............................ 55 3.5 Materials and Methods...................... 56 3.5.1 Protein Extraction and MALDI-Phyloproteomics.... 56 3.5.2 Lipophilic Extraction for Molecular Networking.... 57 3.5.3 MS Data Collection and Molecular Network Generation 58 3.6 Acknowledgments........................ 58 Chapter 4 Expanding the Described Metabolome of the Marine Cyanobacterium Moorea producens JHB through Orthogonal Natural Products Workflows 59 4.1 Abstract.............................. 59 4.2 Introduction............................ 60 4.3 Results and Discussion...................... 65 4.3.1 Molecular networking of M. producens JHB....... 65 4.3.2 Purification of analogs from the Jamaicamide and Hec- tochlorin families..................... 68 4.3.3 Genomic Insights into M. producens JHB Natural Products 71 4.3.4 Jamaicamide Halogenation................ 75 4.3.5 Ion Channel Pharmacology of the Jamaicamides.... 79 4.4 Conclusions............................ 80 4.5 Materials and Methods...................... 82 4.5.1 General Experimental Procedures............ 82 4.5.2 Crude Extraction and LCMS............... 82 4.5.3 HPLC Purification.................... 83 4.5.4 Pure Compound HR MS/MS............... 85 4.5.5 Molecular Network.................... 85 4.5.6 Preparation of Mpla Ester Standards........... 86 4.5.7 Stereochemical Analysis of Hectoramide (96)...... 86 4.5.8 Genome sequencing................... 87 4.5.9 Media Experiments.................... 88 4.5.10 Neocortical Neuron Culture............... 88 4.5.11 Intracellular Ca2+ Concentration Measurement..... 89 vii 4.5.12 Intracellular Na+ Concentration Measurement..... 90 4.5.13 Bioassay Data Analysis.................. 90 4.6 Acknowledgements........................ 91 Chapter 5 Synthesis of Marine Natural Products, Balancing Utility Against Avail- ability and Structural Insight...................... 92 5.1 Abstract.............................. 92 5.2 Introduction............................ 93 5.3 Results and Discussion...................... 94 5.3.1 Synthesis of Laurencione................. 94 5.3.2 Synthesis of Gallinamide A............... 95 5.3.3 Synthesis of the Gallinamide Analogs.......... 98 5.4 Conclusions and Future Work.................. 100 5.5 Material and Methods....................... 102 5.5.1 General Procedures.................... 102 5.5.2 Synthesis of the Laurenciones.............. 103 5.5.3 Synthesis of Gallinamide Analogs............ 104 5.6 Acknowledgments........................ 135 Chapter 6 Future Directions for Marine Natural Products Chemistry....... 137 6.1 Abstract.............................. 137 6.2 Introduction............................ 138 6.3 Results and Discussion...................... 139 6.3.1 Molecular Networking Profile of Moorea producens Strains139 6.3.2 Structure Determination of the Shared Metabolite.... 142 6.4 Conclusions............................ 146 6.5 Material and Methods....................... 146 6.5.1 Molecular Network Generation............. 146 6.5.2 NMR Acquisition..................... 147 6.6 Acknowledgments........................ 147 Chapter 7 Conclusions and Final Notes...................... 148 7.1 Introduction............................ 148 7.2 Discussion............................. 149 Appendix A Supplementary Information for Chapter 2............... 153 Appendix B Supplementary Information for Chapter 4............... 172 Appendix C Supplementary Information for Chapter 6............... 205 Bibliography...................................... 236 viii LIST OF FIGURES Figure 1.1: Structures of the didemnins (8-10)....................5 Figure 1.2: Structure of 8-amino-flavin (12) and napyradiomycin (11)........6 Figure 1.3: Structures of the polyenepyrones (15-17) targeted by principal compo- nent analysis................................8 Figure 1.4: Reporductive failure in the copepod life-cycle.............. 11 Figure 2.1: Key 2D-NMR correlations of viequeamide A (25) and viequeamide B (26)..................................... 20 Figure 2.2: Structures of the viequeamides (25-28).................. 23 Figure 2.3: MS2 fragment ions for the isobaric compounds viequeamide E (29) and F(30).................................... 24 Figure 2.4: The prevalence of residues found in the kulolide superfamily...... 26 Figure 3.1: MALDI-MS spectra of Moorea producens 3L.............. 50 Figure 3.2: MALDI-MS spectra of Moorea producens 3L and JHB......... 51 Figure 3.3: MALDI-MS spectra of Cyanobium and Moorea producens JHB..... 52 Figure 3.4: Molecular networking clusters containing the major compounds
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