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I PHASE-TRAFFICKING METHODS in NATURAL PHASE-TRAFFICKING METHODS IN NATURAL PRODUCTS, MODULATORS OF ORGANIC ANION TRANSPORTING POLYPEPTIDES FROM ROLLINIA EMARGINATA, AND PREGNANE AND CARDIAC GLYCOSIDES FROM ASCLEPIAS SPP. BY ©2012 JUAN JOSE ARAYA BARRANTES Submitted to the graduate degree program in Medicinal Chemistry and the Graduate Faculty of the University of Kansas in partial fulfillment of the requirements for the degree of Doctor of Philosophy. ________________________________ Chair ________________________________ ________________________________ ________________________________ ________________________________ Committee members Date Defended: ________________________________ i The Dissertation Committee for Juan Jose Araya Barrantes certifies that this is the approved version of the following dissertation: PHASE-TRAFFICKING METHODS IN NATURAL PRODUCTS, MODULATORS OF ORGANIC ANION TRANSPORTING POLYPEPTIDES FROM ROLLINIA EMARGINATA, AND PREGNANE AND CARDIAC GLYCOSIDES FROM ASCLEPIAS SPP. ________________________________ Chair ________________________________ ________________________________ ________________________________ ________________________________ Committee members Date approved:_______________________ ii ABSTRACT Phase-Trafficking Methods in Natural Products, Modulators of Organic Anion Transporting Polypeptides from Rollinia emarginata, and Pregnane and Cardiac Glycosides from Asclepias spp. Juan J. Araya Barrantes, Ph. D. The University of Kansas, 2012 For decades, chemists and medicinal chemists have found in nature the source of inspiration for drug discovery and development. This work describes several aspects of the interaction between the fields of natural products and medicinal chemistry, from isolation and characterization of bioactive molecules to semi-synthetic analogs preparation. A new phase-trafficking approach for acidic, basic, and neutral compounds separation from organic plant extracts was developed, validated and successfully applied to crude plant extracts. This new method could be applied to natural extracts of diverse origin in order to generate better quality samples for initial bioassays. Furthermore, this new catch-and-release methodology allowed the isolation and identification of three compounds new to the literature from the extensively studied ginger rhizomes. Using a more traditional bioassay guided fractionation, we have identified six small-molecules from Rollinia emarginata that modulate organic anion transporting polypeptide´s (OATPs) function. The results of this study show that diverse plant materials are a promising source for the isolation of OATP modulating compounds, and that a bioassay-guided approach can be used iii to efficiently identify selective OATP modulators. In addition, a 1H NMR-based metabolomic approach was used as a dereplication tool to study the effect of aqueous green tea extracts on OATP1B1-mediated uptake of estrone-3-sulfate. Our findings suggested that not only the gallate catechins were important for the observed uptake inhibition, but also compounds theogalline and 3-p-cumaroyl quinic acid could have been involved. A screening against breast cancer cell line Hs578T was conducted with ten plant species from the Asclepiadaceae family and, based on our findings, three plants were selected for detailed investigation: Asclepias verticillata, Asclepias syriaca, and Asclepias sullivantii. As a result, a total of 46 compounds were isolated and identified, half of which represented novel structures. The isolates showed a wide variety of structures including pregnane and cardiac glycosides, pentacyclic triterpenes, glycosylated flavonoids and lignans, among others. Furthermore, a group of cardiac glycosides were found to have strong cytotoxicity selected breast cancer cell lines. Finally, using a semi-synthetic approach, cardiac glycoside analogs with modifications in the butenolide ring were pursued in order to better understand their SAR. Starting from the commercially available trans-aldosterone, the cardiac glycoside core was built up using a microwave-promoted allylic oxidation using SeO2 (Riley oxidation). In addition, a microwave- promoted Miyaura-Suzuki cross-coupling was utilized to obtain the desired 17β-aryl analogs. iv ACKNOWLEDGEMENTS During my time at the University of Kansas, I have been blessed with the support of my mentors, coworkers, friends, and family; without them this work would never have been possible. First, I would like to thank Professor Barbarara Timmermann who has been an extraordinary doctoral research advisor throughout these years. She has been a constant source of guidance and encouragement and I am immeasurably grateful. I am also greatly thankful to the faculty of the department of Medicinal Chemistry and Chemistry at the University of Kansas who have shown to me the wonderful world of Medicinal Chemistry. Professor Thomas Prisinzano, in particular, had opened the doors of his laboratory where I have been able to learn the "tweaks and tricks" of organic synthesis. I would like to give special thanks to Professor Lester Mitscher as I was tremendously fortunate to work on one of his many brilliant research ideas. I also thank Professors Barbara Timmermann, Lester Mitscher, Thomas Prisinzano, Bruno Hagenbuch, and Kelly Kindscher for graciously serving as members of my oral examination committee. I thank Dr. David VanderVelde (now at California Institute of Technology), Dr. Justin Douglas, and Mrs. Sarah Neuenswander from the Nuclear Magnetic Resonance facilities for providing an outstanding service and always offering a helping hand. Also, I would like to thank Dr. Todd Williams and the personnel at the Mass Spectrometry Laboratory as well as Dr. Victor Day from the X-Ray Crystallography Laboratory for their invaluable help in my research work. I have to thank Dr. Peter McDonald from the High-Throughput Screening Laboratory for conducting all the cytotoxicity assays and providing me great insight into the cellular-based v bioassays. Last but not least, I need to thank Jane Buttenhoff, Norma Henley, William Orth, Stuart Mills, Grace Hutchins, and Revellia Rasmussen in the Department of Medicinal Chemistry for dealing with all administrative issues related with this project. The members in the groups of Professors Timmermann and Prisinzano as well as my fellow graduate students have helped and inspired me in my studies. Especially, I thank Dr. Huaping Zhang for his mentorship and guidance during my research. Financial support is has been provided by the National Institutes of Health (NIH) ICBG grant 5 UO1 TW000316, NCCAM/ODS grant 1R21AT004182-01A2; University of Kansas Center for Research project 2506014-910/099; and the Kansas Bioscience Authority (KBA) and Center for Heartland Plant Innovations (HPI) grant IND0061464. Also, I personally thank the Fulbright- LASPAU fellowship and the University of Costa Rica for partially supporting my studies. Finally, I need to give my gratitude to my family and friends. My parents, far away in Costa Rica, have taught me values that helped me succeed including perseverance and responsibility. My friends in Lawrence became family away from home; their support was vital during this journey. I also whish to thank my wife and best friend, Angie, for her love, patience, and support who gave up everything to join me in this adventure and the last five years have been undoubtedly the best time of our lives as we were blessed with the arrival of our beloved son, Jose Pablo. vi To Angie and Jose Pablo vii TABLE OF CONTENTS ABSTRACT ............................................................................................................................... iii ACKNOWLEDGEMENTS ......................................................................................................... v TABLE OF CONTENTS ......................................................................................................... viii LIST OF FIGURES .................................................................................................................. xiv LIST OF TABLES .................................................................................................................. xxiii LIST OF COMPOUNDS ....................................................................................................... xxvii ABBREVIATIONS .............................................................................................................. xxxiii 1. INTRODUCTION.............................................................................................................. 1 1.1. Relevance of natural products in medicinal chemistry ............................................... 2 1.2. Natural products-based drug discovery ....................................................................... 5 1.2.1. Biomass access: selection, collection, and identification ............................................ 6 1.2.2. Extraction .................................................................................................................... 6 1.2.3. Screening ..................................................................................................................... 7 1.2.4. Bioassay-guided fractionation and isolation ............................................................... 8 1.2.5. Dereplication ............................................................................................................... 8 viii 1.2.6. Structure elucidation ...................................................................................................
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