The Design, Synthesis and Biological Evaluation of Mycobacterium tuberculosis Proteasome Inhibitors Open Access
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Abstract of Dissertation The Design, Synthesis and Biological Evaluation ofMycobacterium tuberculosis Proteasome InhibitorsTuberculosis (TB), caused by the bacteria Mycobacterium tuberculosis (Mtb), is the second leading cause of death worldwide due to an infectious disease. The World Health Organization (WHO) estimated that in 2012 nine million people acquired TB and almost two million people died of the disease. New drug discovery to combat TB has been slow, limiting the number of available antitubercular drugs and resulting in the emergence of drug resistant strains of TB. Mtb is one of the few bacteria known to contain proteasomes, large enzymatic complexes used in cellular protein degradation. Analogous to using proteasome inhibitors as chemotherapy agents treating human cancers, inhibiting the Mtb proteasome has been shown to kill Mtb and could be a novel method of TB treatment. This project investigated the design, synthesis and biological activity of dipeptide boronates as Mtb proteasome inhibitors. Chapter One describes the course of TB as a disease and its effects on the human body. Scientific research, including the work of 19th and 20th century scientists to identify the bacteria and treat TB as well as current methods of diagnosis and treatment are discussed. Chapter Two reviews the eukaryotic Ubiquitin-Proteasome System (UPS) and Prokaryotic-Proteasome System (PPS) and compares the two pathways. Individual components of the pathways are examined for their structure, function and assembly. Chapter Three presents proteasome inhibitors used in the treatment of human cancers. Discussed are natural product templates, first-generation synthetic inhibitors, and second-generation inhibitors currently in clinical trials. Finally, the current literature describing inhibitors of the Mtb proteasome is presented. Chapter Four details the research hypothesis, goals and objectives of this project. The objectives are based on Mtb and yeast crystal structure evaluations, in silico dipeptide boronate modeling studies and inhibitor template considerations. Chapter Five begins with a brief review of prior work on the synthesis of peptide organoboronate inhibitors. Following this, our synthetic strategy, reaction methods and synthetic results are presented. Process optimization and alternate reaction conditions that were considered are discussed.Chapter Six reports the data from a series of assays evaluating the biological activity of our compounds. Data from enzyme inhibition and antitubercular assays using our dipeptide boronate inhibitors are analyzed and compared with known antitubercular drugs and proteasome inhibitors. The selectivity of our compounds for inhibition of the Mtb proteasome over the human homologue is evaluated.Chapter Seven summarizes the research of this project and discusses possible future directions for the continued design and synthesis of dipeptide boronate Mtb proteasome inhibitors. Alternate components of the PPS and compounds with novel architecture are assessed as potential antitubercular targets and Mtb inhibitors, respectively.