异蝎核的模块化合成被探索作为快速开发钌基治疗剂的工具。从一系列结构多样的醇-NN配体开始，合成、表征和评估了一系列基于异蝎酸酯的钌衍生物，作为乳腺癌治疗的铂疗法的替代品。在体外，使用 UNICAM-1 和顺铂作为金属药物对照，在一系列乳腺癌细胞系中评估了新型衍生物的抗肿瘤活性。通过这种方法，一种基于双金属异蝎酸酯的金属药物 (RUSCO-2) 被确定为该系列的先导化合物，其 IC50 值范围低至 3-5 μM。值得注意的是，RUSCO-2被发现在TNBC细胞系中具有高度细胞毒性，这表明其作用模式不依赖于细胞的受体状态。作为概念证明，并利用所获得的复合物之一的发光特性，通过荧光寿命成像显微镜 (FLIM) 监测人乳腺癌 MCF7 细胞系的摄取，揭示该化合物均匀分布在细胞质中，并且杂蝎酸配体的掺入可保护其免受水性过程、转化为另一个实体或氯基团损失的影响。最后，进行了 ROS 研究，估计了亲脂性，研究了氯/水交换，并进行了模拟生物介质中的稳定性研究，以提出结构-活性关系。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

The modular synthesis of the heteroscorpionate core is explored as a tool for the rapid development of ruthenium-based therapeutic agents. Starting with a series of structurally diverse alcohol-NN ligands, a family of heteroscorpionate-based ruthenium derivatives was synthesized, characterized, and evaluated as an alternative to platinum therapy for breast cancer therapy. In vitro, the antitumoral activity of the novel derivatives was assessed in a series of breast cancer cell lines using UNICAM-1 and cisplatin as metallodrug control. Through this approach, a bimetallic heteroscorpionate-based metallodrug (RUSCO-2) was identified as the lead compound of the series with an IC50 value range as low as 3-5 μM. Notably, RUSCO-2 was found to be highly cytotoxic in TNBC cell lines, suggesting a mode of action independent of the receptor status of the cells. As a proof of concept and taking advantage of the luminescent properties of one of the complexes obtained, uptake was monitored in human breast cancer MCF7 cell lines by fluorescence lifetime imaging microscopy (FLIM) to reveal that the compound is evenly distributed in the cytoplasm and that the incorporation of the heteroscorpionate ligand protects it from aqueous processes, conversion in another entity, or the loss of the chloride group. Finally, ROS studies were conducted, lipophilicity was estimated, the chloride/water exchange was studied, and stability studies in simulated biological media were carried out to propose structure-activity relationships.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.