School of Physical, Environmental and Mathematical Sciences, University of New South Wales, Australian Defence Force Academy, Canberra, ACT 2600, Australia.
Dalton Trans. 2013 Jun 28;42(24):8868-77. doi: 10.1039/c3dt50551k. Epub 2013 May 9.
The effect of human serum on the minimum inhibitory/bactericidal concentrations of the potential antimicrobial agents ΔΔ-{Ru(phen)2}2(μ-bb(n)) {ΔΔ-Rubb(n); where phen = 1,10-phenanthroline, bb(n) = 1,n-bis[4(4'-methyl-2,2'-bipyridyl)]-alkane for n = 12 and 16} against four strains of bacteria--Gram positive Staphylococcus aureus and methicillin-resistant S. aureus (MRSA), and Gram negative Escherichia coli and Pseudomonas aeruginosa--has been determined. The results demonstrated that the ruthenium(ii) complexes have significantly decreased in vitro activity in serum. Fluorescence spectroscopy was used to confirm that the decrease in antimicrobial activity was due to the strong binding of the ruthenium complexes with the serum proteins human serum albumin (HSA) and transferrin. A series of ruthenium complexes showed stronger binding to HSA than apo-transferrin but comparable or less than with holo-transferrin, with the binding affinity to all three proteins decreasing in the order trinuclear > dinuclear > mononuclear. The dinuclear complex ΔΔ-Rubb12 displaced warfarin from HSA, tentatively suggesting that the ruthenium complexes bind at or near the warfarin-binding site, Sudlow's site 1. The binding of ΔΔ-Rubb12 and ΔΔ-Rubb16 to the macrocyclic host molecule cucurbit[10]uril (Q[10]) was examined by NMR spectroscopy. The large upfield (1)H NMR chemical shift changes observed for the methylene protons in the bridging ligands upon addition of Q[10], coupled with the observation of a range of intermolecular ROEs in ROESY spectra, indicated that the dinuclear complexes bound Q[10] with the bridging ligand within the cavity and the metal centres positioned outside the portals. NMR and fluorescence spectroscopy demonstrated that the Q[10]-encapsulated ruthenium complexes directly bound HSA, and with similar affinity to the corresponding free metal complexes.
已确定人血清对潜在抗菌剂 ΔΔ-{Ru(phen)2}2(μ-bb(n)) {ΔΔ-Rubb(n)；其中 phen = 1,10-菲咯啉，bb(n) = 1,n-双[4(4'-甲基-2,2'-联吡啶)]-链烷烃，n = 12 和 16} 对四种细菌--革兰氏阳性金黄色葡萄球菌和耐甲氧西林金黄色葡萄球菌（MRSA）以及革兰氏阴性大肠杆菌和铜绿假单胞菌--的最低抑菌/杀菌浓度的影响。结果表明，钌(ii)配合物在血清中的体外活性显著降低。荧光光谱用于证实抗菌活性的降低是由于钌配合物与血清蛋白人血清白蛋白（HSA）和转铁蛋白的强结合。一系列钌配合物与人血清白蛋白的结合比脱铁转铁蛋白更强，但与全铁转铁蛋白的结合相当或低于全铁转铁蛋白，与所有三种蛋白质的结合亲和力按三联体>二联体>单体的顺序降低。二联体配合物 ΔΔ-Rubb12 从 HSA 中置换华法林，这表明钌配合物结合在华法林结合部位或附近，即 Sudlow 的部位 1。通过 NMR 光谱研究了 ΔΔ-Rubb12 和 ΔΔ-Rubb16 与大环主体分子葫芦[10]脲（Q[10]）的结合。当添加 Q[10]时，桥连配体的亚甲基质子观察到的较大的向上（1）H NMR 化学位移变化，以及 ROESY 谱中观察到的一系列分子间 ROE，表明二联体配合物将桥连配体与金属中心一起结合在腔内，位于腔门之外。NMR 和荧光光谱表明，Q[10]包封的钌配合物直接与 HSA 结合，与相应的游离金属配合物具有相似的亲和力。
