Pyridylphosphinate metal complexes: synthesis, structural characterisation and biological activity

Abstract

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 η⁶-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 pK_a 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.