A short and scalable synthesis of naamidine A, a marine alkaloid with a selective ability to inhibit epidermal growth factor receptor (EGFR)-dependent cellular proliferation, has been achieved. A key achievement in this synthesis was the development of a regioselective hydroamination of a monoprotected propargylguanidine to deliver N3-protected cyclic ene-guanidines. This permits the extension of this methodology to prepare N2-Acyl analogues in a fashion that obviates the troublesome acylation of the free 2-aminoimidazoles, which typically yields mixtures of N2- and N2,N2-diacylated products.

We present data demonstrating the natural product mimic, zinaamidole A (ZNA), is a modulator of metal ion homeostasis causing cancer-selective cell death by specifically inducing cellular Zn 2+ uptake in transformed cells. ZNA's cancer selectivity was evaluated using metastatic, patient derived breast cancer cells, established human breast cancer cell lines, and three-dimensional organoid models derived from normal and transformed mouse mammary glands. Structural analysis of ZNA demonstrated that the compound interacts with zinc through the N 2 -acyl-2 aminoimidazole core. Combination treatment with ZnSO 4 strongly potentiated ZNA's cancer specific cell death mechanism, an effect that was not observed with other transition metals. We show that Zn 2+ -dyshomeostasis induced by ZNA is unique and markedly more selective than other known Zn 2+ interacting compounds such as clioquinol. The in vivo bioactivity of ZNA was also assessed and revealed that tumor-bearing mice treated with ZNA had improved survival outcomes. Collectively, these data demonstrate that the N 2 -acyl-2aminoimidazole core of ZNA represents a powerful chemotype to induce cell death in cancer cells concurrently with a disruption in zinc homeostasis.

A regioselective base-mediated cyclization of mono-N-acylpropargylguanidines is reported. A related Ag(I)-catalyzed hydroamination strategy was recently employed to yield N3-Cbz-protected ene-guanidines, which found utility in the synthesis of naamidine A. Herein, we report the base-catalyzed hydroamination of mono-N-acylpropargylguanidines, which proceeds with the opposite regiochemistry to deliver isomerized N2-acyl-2-aminoimidazoles with broad substrate scope, circumventing the problematic regiospecific acylation of free 2-aminoimidazoles.

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