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Chemical Investigations of Fungal Natural Products for Drug Discovery Danielle H University of South Florida Scholar Commons Graduate Theses and Dissertations Graduate School July 2017 Chemical Investigations of Fungal Natural Products for Drug Discovery Danielle H. Demers University of South Florida, [email protected] Follow this and additional works at: http://scholarcommons.usf.edu/etd Part of the Chemistry Commons Scholar Commons Citation Demers, Danielle H., "Chemical Investigations of Fungal Natural Products for Drug Discovery" (2017). Graduate Theses and Dissertations. http://scholarcommons.usf.edu/etd/6825 This Dissertation is brought to you for free and open access by the Graduate School at Scholar Commons. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Scholar Commons. For more information, please contact [email protected]. Chemical Investigations of Fungal Natural Products for Drug Discovery by Danielle H. Demers A dissertation submitted in partial fulfillment of the requirement for the degree of Doctor of Philosophy Department of Chemistry College of Arts and Sciences University of South Florida Major Professor: Bill J. Baker, Ph.D. Lindsey N. Shaw, Ph.D. James W. Leahy, Ph.D. Edward Turos, Ph.D. Date of Approval: June 27, 2017 Keywords: screening, epigenetic modification, Phomopsis , Penicillium , ESKAPE, leishmaniasis Copyright © 2017, Danielle H. Demers Dedication This work is wholehear tedly dedicated to my incredible family. To say I wish to thank my parents, Chris and Sharon, hardly sounds like enough . In my entire life, t hese two have never doubted me for one second. I would not be the person I am today without their ceaseless support, enc ouragement, sacrifice, and love. Truly, this body of work would not exist were it not for all the phone calls, packages, emails, and visits that made Florida feel a little less far f rom home over the past 6 years. I am so lucky to have them, and the amazing family they have built, in my corn er. To my brothers, Luke and CJ, and my “older sister” Cyndi, thank you for your love, friendship, and pat ience with me over these years. T o the friends and extended family members that are far too numerous to list here (such is the blessing and the curse of such a beautifully large, crazy clan) , thank you for your continued interest, compassion, and support . And finally , to Kieryn Emilee, I dedica te this to you, and hope you always remember that nothing and no one can keep you from your dreams. “Keep moving forward” ~ Walt Disney Acknowledgements This dissertation is built on the shoulders of giants and the work of an army of scientists. I must first and foremost thank Dr. Bill Baker for sharing his knowledge, financial support, and for telling me “no” when I did not want to hear it. I was blessed with amazing experiences, opportunities, and life lessons during my years here, and none of it would have been possible without you . To my committee, past and present Baker L ab members, collaborating teams at USF and beyond , and my many undergrads : thank you for your help, enthusiasm, and dedication to this work. No scientist works alone and I am so grateful to have met and worked with so many excellent researchers . To the colleagues who became friends, and the friends who became family: I would not have survived without you. There are so many people who deserve to be acknowledged for their comradery over these past 6 years, and though I cannot possibly list you all, please know that your contributions to my life here at USF do not go unrecognized. Thank y ou for turning Florida into my second home. I cannot wait to see what comes next for all of us. Table of Contents List of Tables ................................ ................................ ................................ ........................... iii List of Figures ................................ ................................ ................................ ........................... iv List of Schemes ................................ ................................ ................................ ......................... ix List of Abbreviations and Units ................................ ................................ ................................ x Abstract ................................ ................................ ................................ ................................ xiii Chapter 1. An Introduction to Marine Natural Product Drug Discovery .............................. 1 1.1. Why Natural Products ................................ ................................ ............................... 1 1.2. Sources of Marine Natural Products ................................ ................................ .......... 2 1. 2.1. Marine M acro - organism s ................................ ................................ ............ 2 1.2.2. Marine M icro - organisms ................................ ................................ ............ 3 1.2.3. Marine P lant E ndophytes ................................ ................................ ............ 4 1.2.4. Collection Locations and Non - marine S ources ................................ ........... 5 1.2.4.1. Antarctica ................................ ................................ .................... 5 1.2.4.2. Florida ................................ ................................ ......................... 7 1.2.4.3. Terrestrial and fresh water environments ................................ ...... 8 1.3. Approaches Towards the Isolation of Microbial Natural Products ............................. 9 1.3.1. Collection and I solation ................................ ................................ .............. 9 1.3.2. Culture T echniqu e s ................................ ................................ ................... 10 1.4. Drug Discovery Targets ................................ ................................ .......................... 11 1.4.1. The ESKAPE P athogens ................................ ................................ ........... 13 1.4.2 . Leishmania donovani ................................ ................................ ................ 13 1.4.3. Mycobacterium tuberculosis ................................ ................................ ..... 13 1.4.4. Clostridium difficile ................................ ................................ .................. 14 1.4.5. Naegleria fowleri ................................ ................................ ...................... 14 1.4.6. Cancer T argets ................................ ................................ ......................... 15 1.5. Future Directions ................................ ................................ ................................ .... 15 1.6. References ................................ ................................ ................................ .............. 16 C hapter 2. New Bioactive Meroterpenes from Phomopsis sp. ................................ ............... 23 2 .1 . BB11 - 2 Isolation ................................ ................................ ................................ ..... 23 2 .2 . Initi al Bioactivities and Scale - up ................................ ................................ ............. 24 2 .3 . Compound Isolation and Structure Elucidation ................................ ....................... 25 2 .4 . Bioactivities ................................ ................................ ................................ ............ 38 2 .5 . Future Directions ................................ ................................ ................................ .... 40 2 .6 . References ................................ ................................ ................................ .............. 40 i Chapter 3 . The Creation of a Large Fungal Isolate and Extract Library ............................ 42 3 .1 . Curating a Fungal Library ................................ ................................ ....................... 42 3 .2 . Screening Protocols, Accomplishments ................................ ................................ ... 45 3 .3 . Metabolomic Analysis ................................ ................................ ............................ 47 3 .4 . Training Set Results ................................ ................................ ................................ 50 3 .5 . Future Directions ................................ ................................ ................................ .... 52 3 .6 . References ................................ ................................ ................................ .............. 52 Chapter 4 . A New Citreohybrid d ione Discovered Via Epige netic Modification .................. 54 4.1 . Citreohybridones and Citreohybriddiones ................................ ............................... 54 4.2 . KML12 - 14MG - B2a I solation ................................ ................................ .................. 55 4.3 . Initial Bioactivities, Scale - up, Epigenetic Modification , and Identification .............. 57 4.4 . Compound Isolation and Structure Elucidation ................................ ....................... 59 4.5 . Future Directions ................................ ................................ ................................ .... 63 4.6 . References ................................ ................................ ................................ .............. 64 Appendix A: Experime ntal and Supporting Data for Chapter 2 ................................ .......... 65 Appen dix B: Experime ntal
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