| Description |
This dissertation concerns the development of methods to synthesize and study N2-acyl-2-aminoimidazole ionophores inspired by the marine natural product, naamidine A. This marine alkaloid was isolated in 1987 alongside related decorated 2-aminoimidazoles, as well as mixed dimeric complexes with Zn2+. Though the relationship between the secondary mebolite and zinc is still not defined in the context of the sponge, we hypothesize that this class of alkaloid may act as siderophores for zinc in marine environments. Our initial interest in naamidine A stemmed from its two distinct reported mechanisms of action in cancer cells: Its ability to act as an extracellular regulated kinase (ERK) agonist and its ability to induce apoptosis in epidermoid carcinoma cells. We believed that the apoptotic phenotype could arise from mitochondrial membrane depolarization reported, and sought to determine if naamidine A's direct interaction with endogenous Zn2+ pools could be responsible. Our attempts to decouple these mechanisms of action required the development of robust synthetic methodology to access N2-acyl-2-aminoimidazoles, which were designed to interact with Zn2+ in a fashion similar to naamidine A, but avoid the structural motifs we believed gave rise to ERK modulation. Initial evaluation of this class of N2-acyl-2-aminoimidazoles was conducted by the Welm group at the Huntsman Cancer Institute in a screening effort to identify new scaffolds that are able to selectively inhibit the growth of primary cells isolated from patients with metastatic, refractory breast cancer. One such compound, later given the name iv zinaamidole, was identified by the screen as selective and potent against multiple patient-derived cell lines. Further profiling revealed that zinaamidole is able to cause cell death through a nonapoptotic pathway, but instead causes upregulation of multiple metal-trafficking proteins. Given naamidine A's relationship with zinc, we explored zinaamidole's interaction with zinc in the context of established breast cancer cell lines. Zinaamidole is able to deliver superstoichiometric payloads of zinc into transformed breast cancer cells, regardless of receptor subtype classification, defining it as a zinc ionophore. The experiments herein describe a synthesis-driven approach towards understanding the complex chemical properties that underpin ionophores in the context of cancer, and offer insight into cellular mechanisms affected by zinc dyshomeostasis. |
