Development of Novel Cancer Treatments Targeting Pyrimidine Nucleotide Biosynthesis and the Synthesis of Tool Compounds for Enhanced Profiling of Oxidative Post-Translational Modifications
This dissertation details the chemistry work that has been done to support the Radu lab’s cancer research efforts. Although cancer research is typically performed via cell cultures, tissue cultures, mice studies, etc., there are many aspects that require specialized chemistry to accomplish. What is sometimes overlooked or quickly summarized is the tedious chemistry groundwork that may lead to the invention of a successful drug or tool compound, enabling interesting biology to be studied or observed. Even though publications generally focus on successful final outcomes, failed cases can provide important lessons going forward. For example, sometimes new compounds no longer target the desired protein, but can still treat cancer or elicit intriguing biological outcomes. Whether or not the projects detailed in this dissertation were successful is subjective and may not be determined in a short period of time. Nonetheless, the accurate documentation of this work hopefully may provide the opportunity for other scientists to learn from and build upon. This dissertation outlines the results of three independent projects all revolving around the development of novel cancer therapies. In Chapter One, new inhibitors of deoxycytidine kinase that were designed to improve upon drug-like properties such as solubility or ease of synthesis will be introduced. The new compounds will be compared to the clinically-viable lead, (R)-DI-87, and assessed in terms of potency, solubility, and ease of synthesis. At the end of Chapter One, how a dCK inhibitor possessing an amine handle, NMc-77, was used to construct potential deoxycytidine kinase degraders will also be described. In Chapter Two, HCT13, a thiosemicarbazone derivative, was made initially to improve upon Triapine’s ribonucleotide reductase-inhibiting activity. Surprisingly, small structural changes abolished the compound’s activity against ribonucleotide reductase, yet HCT13 remained a potent and effective drug against aggressive leukemia in mouse models. Lastly, Chapter Three will detail efforts to synthesize cysteine labeling compounds that can enable high-throughput studies of cysteine oxidative post-translational modifications. These tool compounds may help scientists gain more insight into various treatment efficacies and resistance mechanisms by elucidating changes in cysteine-mediated redox signaling.