Palmeira-Mello Marcos V, Mesdom Pierre, Burckel Pierre, Hidalgo Samia, Blacque Olivier, Gasser Gilles, Batista Alzir A
Departament of Chemistry, Universidade Federal de São Carlos, 13565-905, São Carlos, SP, Brazil.
Chimie ParisTech, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, PSL University, 75005, Paris, France.
Chembiochem. 2025 Jan 14;26(2):e202400734. doi: 10.1002/cbic.202400734. Epub 2025 Jan 10.
In this work, we studied six Ruthenium(II)-diphosphine compounds containing different mercapto ligands (N-S), with general formula [Ru(N-S)(dppm)]Cl (dppm=1,1-bis(diphenylphosphino)methane). These compounds were characterized by several techniques (NMR [H, P(H), and C], HRMS, IR, UV-Vis and XRD) and their purity confirmed by elemental analysis. DLS experiments revealed low diameters and polydispersity indexes, and positive log P values in n-octanol/PBS indicated their preference for the organic phase. In general, these compounds are stable in different media over 48 h. Cytotoxicity experiments revealed promising IC values on A549 breast cancer cells, 0.48 μM and 0.80 μM for [Ru(mtz)(dppm)]Cl (1) and [Ru(mmi)(dppm)]Cl (2), respectively (mtz and mmi are 2-mercapto-2-thiazoline and mercapto-1-methylimidazole in their deprotonated form, respectively). Clonogenic and migration experiments indicated their antiproliferative and anti-migratory capacity. ICP-MS results indicated their cellular accumulation in the nucleus, with little amounts in mitochondria. No covalent DNA binding was observed by ICP-MS. JC-1 and cell Mito Stress test confirmed mitochondrial dysfunction, which was verified by mitochondrial membrane potential uncoupling and drastic alterations in the oxygen consumption rate. Taken together, our results provide crucial insights regarding the anticancer potential of ruthenium(II)-phosphine compounds.
在本研究中，我们研究了六种含有不同巯基配体（N-S）的钌（II）-二膦化合物，通式为[Ru(N-S)(dppm)]Cl（dppm = 1,1-双（二苯基膦基）甲烷）。这些化合物通过多种技术（核磁共振氢谱、磷谱和碳谱、高分辨质谱、红外光谱、紫外可见光谱和X射线衍射）进行了表征，并通过元素分析确认了其纯度。动态光散射实验显示其粒径较小且多分散指数较低，正辛醇/磷酸盐缓冲液中的log P值为正，表明它们倾向于有机相。一般来说，这些化合物在不同介质中48小时内稳定。细胞毒性实验显示，[Ru(mtz)(dppm)]Cl（1）和[Ru(mmi)(dppm)]Cl（2）对A549乳腺癌细胞的半数抑制浓度（IC）值分别为0.48 μM和0.80 μM（mtz和mmi分别是去质子化形式的2-巯基-2-噻唑啉和巯基-1-甲基咪唑）。克隆形成和迁移实验表明它们具有抗增殖和抗迁移能力。电感耦合等离子体质谱结果表明它们在细胞核中积累，而在线粒体中的含量很少。电感耦合等离子体质谱未观察到共价DNA结合。JC-1和细胞线粒体应激试验证实了线粒体功能障碍，这通过线粒体膜电位解偶联和氧消耗率的剧烈变化得到验证。综上所述，我们的研究结果为钌（II）-膦化合物的抗癌潜力提供了重要见解。
