Analytical investigation of the proteasome inhibitor Bortezomib and the total synthesis of specialized pro-resolving lipid mediators

This body of work seeks to use synthetic and analytical chemistry techniques to improve the understanding of biologically interesting compounds. This has been completed in multiple projects investigating the anti‐cancer therapeutic Bortezomib and natural metabolites of essentially fatty acids with high potency promoting the resolution of inflammation and tissue regeneration. ❧ Chapter 1 provides a detailed analytical investigation towards the characterization and evaluation of the interactions of FDA approved anti‐cancer therapeutic Bortezomib with dietary polyphenols. The green tea polyphenol epigallocatechin‐3‐gallate was reported to effectively antagonize the ability of Bortezomib to induce apoptosis in cancer cells. This interaction was attributed to the formation of a covalent adduct between a phenolic moiety of epigallocatechin‐3‐gallate with the boronic acid group of Bortezomib. However, the structural details of this boron adduct and the molecular factors that contribute to its formation and its ability to inhibit Bortezomib’s activity remained unclear. This work describes the use of NMR spectroscopy to characterize the structures and properties of the boron adducts of epigallocatechin‐3‐gallate and related polyphenols. ❧ The remaining chapters are dedicated to the design, synthesis and activity of compounds enzymatically produced from essential omega‐3 and omega‐6 fatty acids during a host’s inflammatory immune response, and their synthetic analogs. This includes a brief review of the class of specialized pro‐resolving lipid mediators (SPMs) including their isolation, identification, and biological activity. It has long been postulated that fatty acids such as docosahexaenoic acid present a variety of health benefits including the production of SPMs containing anti‐inflammatory, pro‐resolving, and tissue regenerative properties. This work helps support these claims by producing the design and synthesis of several SPMs derived from docosahexaenoic acid providing a molecular basis for some of theses health effects. Including the design and synthesis of resolvin D4, aspirin‐triggered resolvin D4, maresin 1, maresin 2, maresin conjugate in tissue regeneration 1 and 2, 16S‐17S‐epoxy‐neuroprotectin D1, and a library of benzo SPM based analogs.