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 Zn2+-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 N2-acyl-2-aminoimidazole core. Combination treatment with ZnSO4 strongly potentiated ZNA's cancer-specific cell death mechanism, an effect that was not observed with other transition metals. We show that Zn2+-dyshomeostasis induced by ZNA is unique and markedly more selective than other known Zn2+-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 N2-acyl-2-aminoimidazole core of ZNA represents a powerful chemotype to induce cell death in cancer cells concurrently with a disruption in zinc homeostasis.

中文翻译：

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受天然产物 Naamidine A 启发的癌症选择性锌离子载体。

我们提供的数据证明天然产物模拟物，zinaamidole A (ZNA) 是金属离子稳态的调节剂，通过特异性诱导转化细胞中的细胞 Zn2+ 吸收，导致癌症选择性细胞死亡。郑州日产的癌症选择性使用转移性、患者来源的乳腺癌细胞、已建立的人类乳腺癌细胞系以及来自正常和转化小鼠乳腺的三维类器官模型进行评估。ZNA 的结构分析表明，该化合物通过 N2-酰基-2-氨基咪唑核与锌相互作用。与 ZnSO4 联合治疗强烈加强了 ZNA 的癌症特异性细胞死亡机制，这是其他过渡金属未观察到的效果。我们表明由 ZNA 诱导的 Zn2+-dyshomeostasis 是独一无二的，并且比其他已知的 Zn2+ 相互作用化合物（如氯碘羟喹）更具选择性。还评估了 ZNA 的体内生物活性，并显示用 ZNA 治疗的荷瘤小鼠的生存结果有所改善。总的来说，这些数据表明，ZNA 的 N2-acyl-2-aminoimidazole 核心代表了一种强大的化学型，可诱导癌细胞死亡，同时破坏锌稳态。