School of Physical, Environmental and Mathematical Sciences, University of New South Wales, Australian Defence Force Academy, Canberra, ACT, Australia.
ChemMedChem. 2011 May 2;6(5):848-58. doi: 10.1002/cmdc.201100053. Epub 2011 Apr 5.
The accumulation, uptake mechanism, cytotoxicity, cellular localisation of-and mode of cell death induced by-dinuclear ruthenium(II) complexes ΔΔ/ΛΛ-{Ru(phen)(2) }(2) {μ-bb(n) } (Rubb(n)), where phen is 1,10-phenanthroline, bb(n) is bis[4(4'-methyl-2,2'-bipyridyl)]-1,n-alkane (n=2, 5, 7, 10, 12 or 16), and the corresponding mononuclear complexes containing the bb(n) ligands, were studied in L1210 murine leukaemia cells. Cytotoxicity increased with linker chain length, and the ΔΔ-Rubb(16) complex displayed the highest cytotoxicity of the series, with an IC(50) value of 5 μM, similar to that of carboplatin in the L1210 murine leukaemia cell line. Confocal microscopy and flow cytometry studies indicated that the complexes accumulate in the mitochondria of L1210 cells, with the magnitude of cellular uptake and accumulation increasing with linking chain length in the bb(n) bridge of the metal complex. ΔΔ-Rubb(16) entered the L1210 cells by passive diffusion (with a minor contribution from protein-mediated active transport), inducing cell death via apoptosis. Additionally, metal-complex uptake in leukaemia cells was approximately 16-times that observed in healthy B cells highlighting that the bb(n) series of complexes may have potential as selective anticancer drugs.
双核钌（II）配合物 ΔΔ/ΛΛ-{Ru(phen)(2) }(2) {μ-bb(n) }（Rubb(n)）中，phen 是 1,10-菲咯啉，bb(n) 是双[4(4'-甲基-2,2'-联吡啶)]-1,n-链烷烃（n=2,5,7,10,12 或 16），其积累、摄取机制、细胞毒性、细胞内定位和诱导的细胞死亡模式-以及相应的单核配合物含有 bb(n)配体，在 L1210 白血病细胞中进行了研究。细胞毒性随连接链长度的增加而增加，ΔΔ-Rubb(16)配合物显示出该系列中最高的细胞毒性，IC50 值为 5 μM，与卡铂在 L1210 白血病细胞系中的毒性相当。共聚焦显微镜和流式细胞术研究表明，这些配合物在 L1210 细胞的线粒体中积累，细胞摄取和积累的程度随金属配合物中 bb(n)桥的连接链长度的增加而增加。ΔΔ-Rubb(16)通过被动扩散（蛋白质介导的主动转运有少量贡献）进入 L1210 细胞，通过细胞凋亡诱导细胞死亡。此外，白血病细胞中金属配合物的摄取量约为健康 B 细胞的 16 倍，这表明 bb(n)系列配合物可能具有作为选择性抗癌药物的潜力。
