School of Science, University of New South Wales Canberra, Australian Defence Force Academy, Canberra, ACT 2600, Australia.
Department of Molecular Biology and Biotechnology, The University of Sheffield, Sheffield, S10 2TN, UK.
Dalton Trans. 2019 Oct 14;48(38):14505-14515. doi: 10.1039/c9dt03221e. Epub 2019 Sep 18.
Linear and non-linear tetranuclear ruthenium(ii) complexes containing the bridging ligand bis[4(4'-methyl-2,2'-bipyridyl)]-1,7-heptane have been synthesised and their biological properties examined. The minimum inhibitory concentrations (MIC) and the minimum bactericidal concentrations (MBC) of the ruthenium(ii) complexes were determined against six strains of bacteria: Gram-positive Staphylococcus aureus (S. aureus) and methicillin-resistant S. aureus (MRSA); and the Gram-negative Escherichia coli (E. coli) strains MG1655, APEC, UPEC and Pseudomonas aeruginosa (P. aeruginosa). The results showed that both tetranuclear complexes had significant antimicrobial activity, with the non-linear (branched) species (Rubb-TNL) having slightly higher activity than the corresponding linear analogue (Rubb-TL). The corresponding toxicity against three eukaryotic cell lines - BHK (baby hamster kidney), Caco-2 (heterogeneous human epithelial colorectal adenocarcinoma) and Hep-G2 (liver carcinoma) - have also been determined. Interestingly, both Rubb-TNL and Rubb-TL were as toxic to the eukaryotic cells as they were to the bacteria, a rarity for kinetically-inert cationic polypyridylruthenium(ii) complexes, and exhibited lower IC values than cisplatin over 24-, 48- or 72-hour incubation times. Fluorescence spectroscopy was used to study the binding of the ruthenium complexes with human serum albumin (HSA). Rubb-TNL and Rubb-TL exhibited strong HSA binding, with equilibrium binding constants in the order of 10 M. Confocal microscopy was used to examine the cellular localisation of Rubb-TNL in BHK cells. The results indicated that the ruthenium complex localised in the nucleolus. Significant accumulation was also observed in the cytoplasm, but not in the mitochondria. Taken together, the results of this study suggest that Rubb-TNL is an unlikely candidate as an antimicrobial agent, but may have potential as an anticancer drug.
已合成了含有桥联配体双[4(4'-甲基-2,2'-联吡啶)]-1,7-庚烷的线性和非线性四核钌(ii)配合物，并研究了它们的生物学性质。测定了六种细菌：革兰氏阳性金黄色葡萄球菌（S. aureus）和耐甲氧西林金黄色葡萄球菌（MRSA）；革兰氏阴性大肠杆菌（E. coli）菌株 MG1655、APEC、UPEC 和铜绿假单胞菌（P. aeruginosa）对钌(ii)配合物的最小抑菌浓度（MIC）和最小杀菌浓度（MBC）。结果表明，两种四核配合物均具有显著的抗菌活性，非线性（支化）物种（Rubb-TNL）的活性略高于相应的线性类似物（Rubb-TL）。还测定了它们对三种真核细胞系 - BHK（幼仓鼠肾）、Caco-2（异质人上皮结直肠腺癌）和 Hep-G2（肝癌） - 的毒性。有趣的是，Rubb-TNL 和 Rubb-TL 对真核细胞的毒性与它们对细菌的毒性一样，这在动力学惰性的阳离子多吡啶钌(ii)配合物中很少见，并且在 24、48 或 72 小时孵育时间内，其 IC 值均低于顺铂。荧光光谱法用于研究钌配合物与人血清白蛋白（HSA）的结合。Rubb-TNL 和 Rubb-TL 与 HSA 具有很强的结合能力，平衡结合常数在 10 M 左右。共聚焦显微镜用于检查 Rubb-TNL 在 BHK 细胞中的细胞定位。结果表明，该钌配合物定位于核仁。细胞质中也观察到明显的积累，但线粒体中没有。总的来说，这项研究的结果表明，Rubb-TNL 不太可能作为一种抗菌剂，但可能有作为抗癌药物的潜力。
