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Post-Synthetic Functionalization of Bioactive Compounds for Rapid Anticancer

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Post-synthetic Functionalization of Bioactive Compounds for Rapid Anticancer Library Expansion and Mechanistic Probe Development for Antimicrobial Resistance DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Chido M. Hambira Graduate Program in Pharmaceutical Sciences The Ohio State University 2018 Dissertation Committee: Professor James Fuchs Advisor Professor David Nagib Co-Advisor Professor Karl Werbovetz Professor Mark Mitton-Fry Copyright by Chido M. Hambira 2018 Abstract Within the realm of medicinal chemistry, not only is it important to optimize for target potency and physicochemical properties of bioactive compounds, but development of enabling technologies that aid in elucidation of biochemical pathways is of equal importance. The body of work contained within this dissertation is a summary of my efforts toward the development of a new C-H functionalization method to facilitate late-stage derivatization of complex bioactive molecules, and post-synthetic modifications of known bioactive compounds of pharmaceutical agents for the development of mechanistic probes. By taking advantage of the versatile reactivity of hypervalent iodine, aided by the labile nature of the ligands, we have harnessed the mild yet enhanced reactivity of iodosobenzene chloroacetate for the chlorination of (hetero)arenes. My key contributions to this project were the discovery of methods amenable to the halogenation of challenging substrates of the (iso)quinoline class of compounds, and the cytotoxic natural product derivate 2”-acetyl phyllanthusmin D, in addition to conducting mechanistic investigations. A significant portion of my doctoral research has been spent developing tool compounds targeting two aspects contributing to the looming public health issue of antimicrobial resistance. The first effort was aimed at the investigation of small molecules transport across Gram-negative bacterial membranes. This work was conducted during a 12-month co-op at GlaxoSmithKline. We explored the feasibility of hijacking a native ii nutrient uptake system, the FadL/FadD-mediated uptake of long chain fatty acids to enable uptake of antimicrobial agents across the Gram-negative membranes. These investigations demonstrated the first proof-of-principle that a post-synthetic attachment of a long fatty acid chain to an antimicrobial agent could facilitate its uptake and cellular accumulation in a FadD-dependent manner. The potential impact of this work lies in conferring broad spectrum activity to Gram-positive only agents by simply attaching a long chain fatty acid recognition element. In addition to the significant drug development challenge imposed by the Gram- negative membranes, resistance mechanisms can develop and propagate within persistent bacterial biofilms impervious to therapeutic intervention. One example of an infection that relies very heavily on the biofilm lifestyle is that caused by S. Typhi, the causative agent of typhoid fever. In an attempt to find new ways to prevent formation of biofilms caused by S. Typhi, structurally distinct compounds, JK-1 and T315, were identified from compound libraries as antibiofilm agents. Several analogues to JK-1 were synthesized in an attempt to build initial structure activity relationships and improve the potency. In addition to analogue development of this class, two T315 mechanistic probes bearing a biotin tag were synthesized and subjected to affinity-based proteomics. These investigations led to the identification of a NADH-dependent oxidoreductase, WrbA as one of the protein targets implicated in the biofilm lifestyle of S. Typhi. This discovery is expected to inform rational analogue design to transform these initial hit compounds into viable drug development leads for the eradication of biofilm-related chronic infections. iii Dedication This document is dedicated to my family. To God be the Glory. iv Acknowledgments I would like to express my deepest gratitude to my advisor Dr. James R. Fuchs for his continued guidance and unwavering support throughout the years. Thank you for challenging me intellectually, encouraging my creativity, and helping me develop into the medicinal chemist that I am today. It has been an absolute joy working with you and I will forever be grateful for laying the foundation necessary for me to address tough research challenges in my professional career moving forward. I am also grateful to my dissertation committee, Dr. David A. Nagib, Dr. Karl Werbovetz, Dr. Mark Mitton-Fry, for their tremendous guidance and supervision during my graduate career and for helping me ensure that this document was a correct and accurate representation of my work and of myself. I am additionally very grateful to both past and present (2012-2018) colleagues in the Fuchs lab for providing an ideal work environment for intellectual stimulation and for all your support in various ways. I will never forget the human touch in this lab. I would specifically like to acknowledge Dr. Nivedita (Nivi) Jena for your supervision in the lab and for being an amazing mentor. I would like to express my gratitude to Dr. John S. Gunn, and his lab, particularly Jasmine Moshiri, and Darpan Kaur for an amazing collaboration for the last 3.5 years. v My sincere gratitude goes to Dr. David A. Nagib for allowing me to learn a new skill-set in your lab. I am grateful for incorporating me into your lab culture and for guiding me throughout the project. The collaborative project in your lab became a labor of love and I am thankful to my colleagues in the Nagib lab for all their support and energetic welcome. I am especially grateful to Stacy Fosu, and Andrew Chen for all their hard-work on the aryl C-H functionalization project and for their patience and support throughout the project. A special thanks goes out to Dr. Lu Wang – you’re the best. Thank you to the Department of Chemistry and Biochemistry for providing a safe and well equipped lab home and for treating me like one of your own. I would like to thank Dr. Fuchs and Dr. Werbovetz and for supporting my one year research experience at GlaxoSmithKline (GSK), PA. This opportunity would not have been possible with the collective effort of you, including various administrators at The Ohio State University College of Pharmacy. I am incredibly grateful to my manager at GSK, Dr. Rob Stavenger, for guiding me throughout this internship, and giving me many opportunities to further develop as a well-rounded scientist. I am very thankful to my coworkers at GSK, Dr. Xiangmin Liao, Dr. Pan Chan and Dr. Nabil Abraham for supporting me during this time. To all my friends at The Ohio State University, my sincere gratitude goes out to you for helping me get through the tough days and the good days. I am especially thankful to Jason Fang, Julian Richard, Janet Antwi, Tehane Ali, Andrew Chen, and Jeremy Lear. I could not have done this without you. You are all very special to me in ways I could never capture with words. From the depth of my heart, thank you. vi To the Ohio State University College of Pharmacy, thank you for providing me with the necessary tools required for the successful completion of this dissertation and for providing financial support throughout my graduate career in the form of the Albeit H. Soloway Graduate Endowed Fund in Pharmacy and Cancer Research, and the Jane Chen Fellowship in Medicinal Chemistry and Pharmacognosy. I am grateful to Dr. Craig McElroy for all your help with instrumental analysis and challenging characterizations Lastly, I would like to thank my family for the inspiration, love, support, prayers, comfort, and well wishes. I hope I have made you proud. Thank you to my extended family members Nancy Ryan and Debbie Splaingard for supporting me and looking out for me throughout the years. I am forever grateful. Thank you to all my friends from back home in Zimbabwe, and from Berea College for keeping me grounded and keeping me laughing. Thank you Jesus for sustaining me throughout this experience. vii Vita 2012................................................................B.A. Chemistry, Berea College 2014................................................................M.Sc. Pharmaceutical Chemistry, The Ohio ........................................................................State University 2012 to present ..............................................Graduate Teaching Associate, Graduate Research Fellow, and Graduate Research Associate, Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University Publications 1. Fosu, S.;† Hambira, C. M.;† Chen, A. D.; Fuchs, J. R.; Nagib, D. A. Site-selective C-H functionalization of (hetero)arenes via transient, non-symmetric iodanes. †Authors contributed equally. Chem – Cell Press, Accepted November 8th, 2018. 2. Moshiri, J. S.; Kaur, D.; Hambira, C. M.; Sandala, J. L.; Koopman, J. A.; Fuchs, J. R.; Gunn, J. S. Identification of a small molecule anti-biofilm agent against Salmonella enterica. Front. Microbiol. 2018, 9, 2804. Fields of Study Major Field: Pharmaceutical Sciences viii Table of Contents Abstract ............................................................................................................................... ii Dedication .......................................................................................................................... iv Acknowledgments..............................................................................................................
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