Cross Jasmine M, Gallagher Natalie, Gill Jason H, Jain Mohit, McNeillis Archibald W, Rockley Kimberly L, Tscherny Fiona H, Wirszycz Natasha J, Yufit Dmitry S, Walton James W
Department of Chemistry, Durham University, South Road, Durham, DH1 3LE, UK.
School of Medicine, Pharmacy and Health, Durham University, Wolfson Research Institute, Queen's Campus, Stockton on Tees, TS17 6BH, UK.
Dalton Trans. 2016 Aug 9;45(32):12807-13. doi: 10.1039/c6dt01264g.
For the first time, a series of 25 pseudo-octahedral pyridylphosphinate metal complexes (Ru, Os, Rh, Ir) has been synthesised and assessed in biological systems. Each metal complex incorporates a pyridylphosphinate ligand, a monodentate halide and a capping η(6)-bound aromatic ligand. Solid- and solution-state analyses of two complexes reveal a structural preference for one of a possible two diastereomers. The metal chlorides hydrolyse rapidly in D2O to form a 1 : 1 equilibrium ratio between the aqua and chloride adducts. The pKa of the aqua adduct depends upon the pyridyl substituent and the metal but has little dependence upon the phosphinate R' group. Toxicity was measured in vitro against non-small cell lung carcinoma H460 cells, with the most potent complexes reporting IC50 values around 50 μM. Binding studies with selected amino acids and nucleobases provide a rationale for the variation in toxicity observed within the series. Finally, an investigation into the ability of the chelating amino acid l-His to displace the phosphinate O-metal bond shows the potential for phosphinate complexes to act as prodrugs that can be activated in the intracellular environment.
首次合成了一系列25种伪八面体吡啶基亚膦酸金属配合物（钌、锇、铑、铱），并在生物系统中进行了评估。每种金属配合物都包含一个吡啶基亚膦酸配体、一个单齿卤化物和一个封端的η(6)键合芳族配体。对两种配合物的固态和溶液态分析揭示了两种可能的非对映异构体之一的结构偏好。金属氯化物在D2O中迅速水解，在水合加合物和氯化物加合物之间形成1:1的平衡比。水合加合物的pKa取决于吡啶基取代基和金属，但对亚膦酸酯R'基团的依赖性很小。在体外对非小细胞肺癌H460细胞进行了毒性测定，最有效的配合物的IC50值约为50μM。与选定氨基酸和核碱基的结合研究为该系列中观察到的毒性变化提供了理论依据。最后，对螯合氨基酸l-His取代亚膦酸酯O-金属键的能力的研究表明，亚膦酸酯配合物有潜力作为前药在细胞内环境中被激活。
