| Description |
The β-Catenin/T-cell factor protein complex is a key component in the Wnt signaling pathway and is found to be dysregulated in cancer. This complex has been the target of many high throughput screening (HTS) campaigns. Although HTS leads have been identified, the lack of knowledge about binding modes of the complex prohibited structural optimizations. The Ji lab has analyzed its crystal structure and identified several key interactions. Using bioisosteric replacement, fragments matching the binding criteria found in the protein structure were designed to mimic the endogenous Tcf. Chapter 1 details the design, synthesis and biology of N-acyl sulfonamide bioisosteres. These molecules mimic 2 carboxylic acid side chains of Tcf with tetrazole and N-acyl sulfonamide moieties. Chapter 2 describes the structural modifications of the previous inhibitors, which allowed installation of other functionalities to engage additional binding elements. Furthermore, biochemical and celluar assays were performed to evaluate their efficacy. Naamidine A is a 2-aminoimidazole alkaloid from the marine sponge Leucetta chagosensis. It displays promising antitumor activities in vitro and in vivo. The Looper lab has reported a modular synthesis towards naamidine A, which allowed access to a range of N2-acyl-2-aminoimidazoles. One of them, termed ZNA, emerged as a hit during a screening effort. ZNA killed chemo-resistant cancer cells while leaving healthy cells unaffected. In collaboration with the Welm lab, we found that ZNA was an ionophore and shuttled Zn2+ iv ions across the cell membrane resulting in zinc dyshomeostasis and apoptosis. However, a preformed dimeric Zn-ZNA complex was biologically inactive, which could have been caused by the insolubility of the complex. In Chapter 3, we synthesized ZNA analogs with solubilizing side chains and evaluated these compounds in different cell lines. Chapter 4 details the biological importance of Zn/ZNA monomeric complexes. We generated several analogs with pendant C4-pyridine side chains that are capable of invoking a tridentate monomeric zinc complex. The preparation of these molecules revealed a mechanistically distinct and stereodefined amino-silylation reaction that has not been previously observed, offering access to new substitution patterns of the cyclic ene-guanidine scaffold. Chapter 5 details the reaction optimization and substrate scope of this transformation. |
