Department of Chemistry and Biochemistry, University of Texas at Arlington, 700 Planetarium Place, Arlington, TX, 76109, USA.
ChemMedChem. 2023 Nov 2;18(21):e202300347. doi: 10.1002/cmdc.202300347. Epub 2023 Aug 29.
Ruthenium(II) trisdiimine complexes of the formula, [Ru(dip) (L-L) ] , where n=0-3; dip=4,7-diphenyl-1,10-phenanthroline; L-L=2,2'-bipyridine (bpy) or 1,10-phenanthroline (phen) were prepared and tested for cytotoxicity in two cell lines (H358, MCF7). Cellular uptake and subcellular localization were determined by harvesting treated cells and determining the ruthenium concentration in whole or fractionated cells (cytosolic, nuclear, mitochondrial/ ER/Golgi, and cytoskeletal proteins) by Ru ICP-MS. The logP values for the chloride salts of these complexes were measured and the data were analyzed to determine the role of lipophilicity versus structure in the various biological assays. Cellular uptake increased with lipophilicity but shows the biggest jump when the complex contains two or more dip ligands. Significantly, preferential cytoskeletal localization is also correlated with increased cytotoxicity. All of the RPCs promote tubulin polymerization in vitro, but [Ru(dip) phen] and [Ru(dip) ] show the strongest activity. Analysis of the pellet formed by centrifugation of MTs formed in the presence of [Ru(dip) phen] establish a binding stoichiometry of one RPC per tubulin heterodimer. Complexes of the general formula [Ru(dip) (L-L)] possess the necessary characteristics to target the cytoskeleton in live cells and increase cytotoxicity, however the nature of the L-L ligand does influence the extent of the effect.
钌（II）三二亚胺配合物的公式为，[Ru（dip）（L-L）]，其中 n=0-3；dip=4,7-二苯基-1,10-菲咯啉；L-L=2,2'-联吡啶（bpy）或 1,10-菲咯啉（phen），被制备并在两种细胞系（H358、MCF7）中进行了细胞毒性测试。通过收集处理过的细胞并通过 Ru ICP-MS 测定整个或分馏细胞（细胞质、核、线粒体/内质网/高尔基体和细胞骨架蛋白）中的钌浓度来确定细胞摄取和亚细胞定位。这些配合物的氯化物盐的 logP 值进行了测量，并对数据进行了分析，以确定亲脂性与结构在各种生物测定中的作用。细胞摄取随着亲脂性的增加而增加，但当配合物含有两个或更多的 dip 配体时，增加幅度最大。值得注意的是，优先细胞骨架定位也与增加的细胞毒性相关。所有 RPC 都能促进微管蛋白在体外聚合，但[Ru（dip）phen]和[Ru（dip）]表现出最强的活性。对在[Ru（dip）phen]存在下形成的 MTs 进行离心形成的沉淀的分析确定了每个 RPC 与每个微管蛋白异二聚体的结合计量比。具有通式[Ru（dip）（L-L）]的配合物具有靶向活细胞中细胞骨架并增加细胞毒性的必要特征，但是 L-L 配体的性质确实会影响影响的程度。
