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Part 1: Design and Synthesis of BRDT Selective Inhibitors As Male Part 1: Design and Synthesis of BRDT Selective Inhibitors as Male Contraceptive Agents Part 2: Focused Library Synthesis for TGR5 (Takeda G Protein-Coupled Receptor 5) Antagonist A Dissertation SUBMITTED TO THE FACULTY OF UNIVERSITY OF MINNESOTA BY Jiewei Jiang IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY Dr. Gunda I. Georg September 2020 ©2020 Jiewei Jiang All Rights Reserved Acknowledgements I would like to express my sincere gratitude to my advisor Dr. Gunda Georg for her mentorship and guidance over the six years. Without her continuous support, I could not have accomplished this journey. Her dedication and enthusiasm to science will always be inspiring me in my future career. My appreciation also goes to Dr. Elizabeth Ambrose, Dr. Carrie Haskell-Luevano, and Dr. William Pomerantz for serving as my committee members. Their insightful suggestions as well as helpful critiques made me become a better scientific researcher. I am deeply grateful to people who made my work herein possible. Thank you to Dr. Timothy Ward and Dr. Peiliang Zhao for their contribution in the synthesis; Dr. Jon Hawkinson, Jonathan Solberg, Dr. Carolyn Paulson, Xianghong Guan for their expertise with fluorescence polarization assay; Dr. Jun Qi and Nana K. Offei-Addo for their expertise with AlphaScreen assay; Dr. Ernst Schönbrunn and Dr. Alice Chan for elegant co-crystal structures; Kristen John for her efforts and discussions about the TGR5 screening. I would like to thank all the Georg group and ITDD members for not only showing me how to do science but also making my everyday life colorful. Thank you to Dr. Sudhakar Jakkaraj and Dr. Narsihmulu Cheryala for generously sharing not only their lab supplies but also knowledge in chemistry; Dr. Sara Coulup, Dr. Erick Carlson, and Brain Gabet for the joyful conversations. A special thank you extends to Dr. Leigh Allen for her great efforts in reviewing, polishing, and finalizing my writings. I firmly appreciate her constructive suggestions and encouragements. I am indebted to Caitlin Boley for her prompt helps since my day one in the university. Last but not the least, I want to thank my parents for their unconditional love and support. No matter how far away we are geographically, my heart is always with you. i Abstract Unintended pregnancies can have significant adverse socioeconomic effects and also health risks for women. One approach to reducing unintended pregnancies is the use of effective contraceptive methods. While women have multiple reversible contraceptive options available, there is an unmet need for safe and reversible male contraceptive methods. Two pharmacological approaches to male contraception have been pursued: disrupting the hormonal milieu (hormonal) or targeting key cellular components in sperm maturation and function (non-hormonal). Chapter 1 provides a brief overview of the current state of these approaches. Because of adverse side effects resulting from hormonal disruption, we aim to develop safe novel non-hormonal male contraceptive agents. To this end, we have targeted an epigenetic reader protein called the testis-specific bromodomain (BRDT), which plays an essential role in spermatogenesis. Chapter 2 describes the initial validation of a tricyclic dihydropyridine hit from a virtual screening campaign as a bromodomain inhibitor. Based on evidence from co-crystal structures and sequence alignments, we hypothesized that engaging the unique Arg54 in the first bromodomain of BRDT (BRDT-1), would achieve BRDT-1 selectivity over other bromodomain isoforms. Guided by this hypothesis, we explored three different structural modifications of the dihydropyridine scaffold: conversion its lactone functionality to a lactam, lactone ring-opening, and conformational restriction of the molecule by macrocyclization. Cellularly active analogs with a greater than 10-fold increase in affinity relative to the original hit compound were obtained. However, the desired BRDT-1 selectivity was not achieved for any of the three subsets. In addition, novel mechanisms of action for targeting BRDT were pursued. We converted potent analogs to proteolysis-targeted chimeras (PROTACs) for selective protein degradation and synthesized bivalent molecules for simultaneous occupancies of two bromodomains. Future work will involve binding assessments of the resultant compounds. Chapter 3 focuses on an inherited genetic disorder, polycystic liver disease (PLD), which currently lacks effective drug therapeutics to halt disease progression. The G protein-coupled receptor TGR5 was identified as strongly associated with PLD, indicating that a potent TGR5 antagonist could be a potential treatment for PLD patients. To develop ii a TGR5 antagonist, we hypothesized that known TGR5 agonists could be converted to antagonists via systematic structural modifications. After selecting the nicotinamide core as our starting point, we used combinatorial chemistry to generate a focused library with more than 100 analogs, which were screened for agonist and antagonist activity. However, the screening results revealed that this library yielded only TGR5 agonists rather than antagonists. Nevertheless, the results provide novel structure-activity relationship insight for TGR5 agonists based on the nicotinamide core. This experiment highlights the need to obtain additional information including the crystal structure of TGR5 and co-crystal structures for future TGR5 antagonist discovery efforts. iii Table of Contents List of Figures .................................................................................................................... ix List of Schemes ................................................................................................................. xii List of Tables .................................................................................................................... xiii List of Compounds ........................................................................................................... xiv List of Abbreviations...................................................................................................... xxiii Chapter 1 Recent Progress in Male Contraception ....................................................... 1 1.1. Social and Scientific Significance of Male Contraceptive Research .................. 1 1.2. Hormonal Male Contraception ........................................................................... 3 1.3. Non-hormonal Male Contraception .................................................................... 7 1.3.1. Retinoic Acid Receptor α ................................................................................ 8 1.3.2. Cation Channels of Sperm .............................................................................. 8 1.3.3. Epididymal Protease Inhibitor ........................................................................ 9 1.4. Summary and Outlook....................................................................................... 10 Chapter 2 Design and Synthesis of BRDT Selective Inhibitors as Male Contraceptive Agents...................................................................................................... 12 2.1. Review of Bromodomain and Extra Terminal Domain (BET) Proteins ........... 12 2.1.1. Epigenetics and Bromodomains ................................................................... 12 2.1.2. The BET Family ........................................................................................... 13 2.1.3. BRDT in Spermatogenesis ............................................................................ 16 2.2. Dihydropyridine Scaffold Identification ........................................................... 18 2.2.1. Hit Identification ........................................................................................... 18 2.2.2. Preliminary Structure-Activity Relationship (SAR) Exploration ................. 19 2.2.3. Binding Mode ............................................................................................... 20 2.2.4. Design Rationale ........................................................................................... 21 iv 2.3. Hit-to-Lead Optimization: Lactam Analogs ..................................................... 23 2.3.1. Docking Prediction ....................................................................................... 23 2.3.2. Chemistry ...................................................................................................... 24 2.3.3. Linker Optimization ...................................................................................... 27 2.3.4. Substitution Effect ........................................................................................ 29 2.3.5. Carboxylate Introduction .............................................................................. 30 2.3.6. Discussion ..................................................................................................... 32 2.4. Hit-to-Lead Optimization: Ring-Open Analogs ................................................ 33 2.4.1. Chemistry ...................................................................................................... 33 2.4.2. Ester Scaffold Exploration ............................................................................ 34 2.4.3. Amide Scaffold Exploration ......................................................................... 35 2.4.4. Co-crystal Structures ....................................................................................
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