Phytochemical Investigation of a Traditional West African Ethnomedicinal Plant, Icacina trichantha BY Brian C Guo B.S., Northwestern University, 2010 M.S., Northwestern University, 2012 DISSERTATION Submitted as partial fulfillment of the requirements for the degree of Doctor of Philosophy in Pharmacognosy in the Graduate College of the University of Illinois at Chicago, 2020 Chicago, Illinois Defense Committee: Dr. Chun-Tao Che, Chair and Advisor Dr. Joanna E. Burdette Dr. Jeremy J. Johnson, Pharmacy Practice Dr. Gail B. Mahady Dr. Brian T. Murphy Dr. Duncan Wardrop, Chemistry DEDICATION I dedicate this to Chicago, the city that has meant so much to me. The city where my father came to continue his work in Traditional Chinese Medicine. The city where my immigrant parents met in a new country. The city where they settled and raised our family. The city where I fell in love with my best friend. The city that will always be with me. ii ACKNOWLEDGEMENTS My first acknowledgement is to my advisor and mentor, Dr. Chun-Tao Che. His guidance and support made me a better student of the world and the natural power that it holds. Under his tutelage, I have grown as a research scientist. Thanks to him, I can proudly consider myself a pharmacognosist. I would also like to thank my dissertation and preliminary examination committee members. Dr. Jeremy Johnson was a helpful advisor and always willing with his time to help my biological experiments. I am also thankful to him for accepting me as a rotational research student. Dr. Brian Murphy and Dr. Joanna Burdette were very passionate instructors and gave me much needed support early in my career. I would also like to thank Dr. Gail Mahady and Dr. Duncan Wardrop for kindly giving their time and advice towards this dissertation. I am particularly grateful to Dr. Alec Krunic for helpful guidance and support in my NMR experiments, as well as being a good friend. I would like to thank Dr. Ben Ramirez and Dr. David Lankin for their assistance with NMR acquisition and interpretation as well. Dr. Dejan Nikolic was a great teacher and friend who was incredibly helpful in mass spectrometry analysis. I would like to express my gratitude to the fellow members of the CT Che research group past and present. I am especially grateful to Dr. Monday M. Onakpa for establishing this international collaboration and without whom none of this work would be possible. I am also particularly grateful to Dr. Ming Zhao who was instrumental for teaching me the skills and techniques needed to study natural products. Dr. Karina Szymulanska-Ramamurthy was a great mentor and friend in my first years as a student. I am thankful to Dr. Zhenlong Wu for his assistance in ECD calculations and Dr. Junfei Zhou, a talented pharmacognosist who provided very helpful advice iii ACKNOWLEDGEMENTS (continued) and guidance. My other fellow lab members were amazing colleagues and friends, including, Dr. Jordan Gunn, Dr. Joshua Henkin, Dr. Bamisaye Oyawaluja, Dr. Xia Wu, Meng Sun, Isoo Youn, Aleksandra Gurgul, Dr. Sharna-kay Daley, Steven Lane, Tomasz Karwas, Samiya Papa, Kevin He, Isheng Hou, Nathan Brown, and Meghna Gill. I would like to thank Dr. Laura Sanchez for allowing access to her lab and mass spectrometry instruments and Valya Petukhova for assisting with training. I am also thankful to Dr. Guido Pauli and Dr. Jonathan Bisson for access and training to the Pauli lab’s resources. I am also grateful to all my fellow classmates and friends that made UIC such a welcoming place to work and study. I would like to thank the many members of the Department of Pharmaceutical Sciences and those associated with the Department for their help and assistance with this work, especially those that contributed their time and resources. I am appreciative for the organizational and logistical help readily given by Elizabeth Ryan. The collaboration with Dr. Katherine Warpeha and her group including Tiffany Wong and Kyo Wakasa was very productive and insightful into the potential of natural products as pesticides and herbicides in agriculture. I am thankful for the members of the Joanna Burdette lab for assisting with cytotoxicity assays including Wei-Lun Chen, Austin Czarnecki, and Brenna Kirkpatrick. I am also thankful to Jeremy Johnson lab member Bhaskar Vemu for assisting with colorectal and prostate cancer cytotoxicity assays. I am very grateful to Dr. Bernie Santarsiero for his assistance in acquiring and analyzing x-ray crystallographic data. Finally, I am thankful to my family and friends for their love and support through the years. The memories and experiences outside of the lab made the work and effort presented here that much more rewarding. iv ACKNOWLEDGEMENTS (continued) My research was supported by the Office of the Director, National Institutes of Health (OD) and National Center for Complementary and Integrative Health (NCCIH) (5T32AT007533) through a T32 pre-doctoral training fellowship and a Oscar Robert Oldberg Prize in Pharmaceutical Chemistry from the Department of Pharmaceutical Sciences in the College of Pharmacy at UIC. I would also like to thank the Pharmacology Industry Internships for PhD Students (PIIPS) Program for supporting my internship with Sirenas MD in San Diego, California. v CONTRIBUTION OF AUTHORS Chapter 1 is an original work by Brian Guo with editing provided by Dr. Chun-Tao Che. Chapter 2 is composed of a published manuscript (Guo, B., et al. J. Nat. Prod. 2016, 79 (7), 1815–1821) of which I am first author. Dr. Monday M. Onakpa assisted with plant material collection and identification. Dr. Ming Zhao and I carried out NMR acquisition and interpretation and writing of the manuscript. Drs. Xiao-Jun Huang and Xiao-Qi Zhang assisted with ECD calculations. Dr. Bernard D. Santarsiero assisted with acquiring and interpreting x-ray crystallographic data. Drs. Wei-Lun Chen, Steven M. Swanson, and Joanna E. Burdette assisted with antiproliferative assays against cancer cell lines. My mentor Dr. Chun-Tao Che assisted with revising of the final manuscript. Chapter 2 is also composed of a published manuscript (Guo, B. et al. Fitoterapia 104612 (2020), 144, 104612) for which I am first author as well and the primary generator of content. Dr. Ming Zhao assisted with NMR interpretation. Dr. Zhenlong Wu assisted with ECD calculations. Dr. Monday M. Onakpa assisted with plant material collection and identification. Dr. Joanna E. Burdette assisted with antiproliferative assays against cancer cell lines. My mentor Dr. Chun-Tao Che assisted with revising of the manuscript. Chapter 3 is composed of a published manuscript (Zhao, M.; Guo, B., et al. J. Nat. Prod. 2017, 80 (12), 3314–3318) of which I am a co-author. Tiffany Wong, Kyo Wakasa, and Dr. Katherine Warpeha assisted with anti-germination assays. The chapter is also composed of cytotoxicity data from a published manuscript (Guo, B., et al. J. Nat. Prod. 2016, 79 (7), 1815–1821) and unpublished biological activity data. Drs. Bhaskar Vemu and Jeremy J. Johnson assisted with antiproliferative assays against cancer cell lines. Chapter 4 is an original work by Brian Guo with editing provided by Dr. Chun-Tao Che. vi TABLE OF CONTENTS CHAPTER PAGE 1. Introduction to Natural Products and Icacina ...........................................................................1 1.1 Background .................................................................................................................2 1.1.1 Pharmacognosy & Phytochemistry .........................................................................2 1.1.2 Medicinal Plants and Botanicals for Drug Discovery..............................................3 1.1.3 African Traditional Medicine (TM) ........................................................................7 1.2 Literature Review ...................................................................................................... 10 1.2.1 Taxonomy of Icacina genus ................................................................................. 10 1.2.2 Morphological description of Icacina trichantha .................................................. 11 1.2.3 Ethnomedicinal use of Icacina species ................................................................. 14 1.2.4 Summary of scientific investigations .................................................................... 20 1.2.5 Chemical constituents .......................................................................................... 20 1.2.6 Biological activities of Icacina genus ................................................................... 32 1.3 Objectives .................................................................................................................. 45 2. Structure Elucidation of Pimarane Diterpenoids .................................................................... 48 2.1 Introduction ............................................................................................................... 49 2.2 Materials and Methods ............................................................................................... 50 2.2.1 General Experimental Procedures. ....................................................................... 50 2.2.2 Plant Material. .................................................................................................... 51 2.2.3 Extraction and Isolation. ................................................................................... 51 2.2.4 Single Crystal X-Ray Structure Determination ....................................................