与正常细胞相比，保钾利尿剂阿米洛利的衍生物优先对肿瘤细胞具有细胞毒性，并且能够靶向对目前使用的治疗剂具有抗性的肿瘤细胞群。然而，阿米洛利临床转化的一个主要障碍是其细胞毒性效力有限，估计IC50值在高微摩尔范围内。在此，我们报告了十种新型阿米洛利衍生物的合成及其对乳腺癌 MCF7（ER/PR 阳性）、SKBR3（HER2 阳性）和 MDA-MB-231（三阴性）细胞系模型的细胞毒性效力的表征。衍生物结构与对这些细胞系的细胞毒性效力的比较强调了完整胍基的重要性，并揭示了药物诱导的细胞毒性和药物亲脂性之间的密切联系。我们证明，我们最有效的衍生物 LLC1 比正常上皮类器官优先对小鼠乳腺肿瘤具有细胞毒性，在代表所有主要亚型的乳腺癌细胞系模型上以个位数微摩尔范围起作用，作用于表现出短暂和持续耐药性的细胞系与化疗药物相比，但在转移性乳腺癌小鼠模型中表现出有限的抗肿瘤作用。尽管如此，我们的观察结果为未来优化对乳腺肿瘤细胞具有优先细胞毒性的阿米洛利化合物提供了路线图。© 2024。作者。

Derivatives of the potassium-sparing diuretic amiloride are preferentially cytotoxic toward tumor cells relative to normal cells, and have the capacity to target tumor cell populations resistant to currently employed therapeutic agents. However, a major barrier to clinical translation of the amilorides is their modest cytotoxic potency, with estimated IC50 values in the high micromolar range. Here we report the synthesis of ten novel amiloride derivatives and the characterization of their cytotoxic potency toward MCF7 (ER/PR-positive), SKBR3 (HER2-positive) and MDA-MB-231 (triple negative) cell line models of breast cancer. Comparisons of derivative structure with cytotoxic potency toward these cell lines underscore the importance of an intact guanidine group, and uncover a strong link between drug-induced cytotoxicity and drug lipophilicity. We demonstrate that our most potent derivative called LLC1 is preferentially cytotoxic toward mouse mammary tumor over normal epithelial organoids, acts in the single digit micromolar range on breast cancer cell line models representing all major subtypes, acts on cell lines that exhibit both transient and sustained resistance to chemotherapeutic agents, but exhibits limited anti-tumor effects in a mouse model of metastatic breast cancer. Nonetheless, our observations offer a roadmap for the future optimization of amiloride-based compounds with preferential cytotoxicity toward breast tumor cells.© 2024. The Author(s).