Electron deficient organometallics as anti-inflamatory drug candidates

Abstract

Half-sandwich complexes of precious metals are a versatile class of organometallic compounds. Their accessibility, robustness, and air-stability are examples of the unique properties that allow their applications in various fields of chemistry (e.g. catalysis), and as anticancer drug candidates. Half-sandwich complexes generally follow the 18-electron rule, although some stable 16-electron (16-e) complexes have been isolated. The latter are generally coordinatively unsaturated leading to potential applications in catalysis and as precursors for 18-electron (18-e) complexes. Six 16-e complexes [Ru(η6-p-cymene)(1,2-benzene-1,2-dithiolato)] (1), [Os(η6-p-cymene) (1,2-benzene-1,2-dithiolato)] (2), [Ir(η5-pentamethylcyclopentadiene) (1,2-benzene-1,2-dithiolato)] (3), [Ru(η6-p-cymene)(1,2-dicarba-closo- dodecaborane-1,2-dithiolato)] (4), [Os(η6-p-cymene)(1,2-dicarba-closo- dodecaborane-1,2-dithiolato)] (5), and [Ir(η5-pentamethylcyclopentadiene)(1,2-dicarba-closo-dodecaborane-1,2-dithiolato)] (6) were synthesised by reactions between 1,2-benzenedithiol (1, 2, 3) or 1,2-dicarba-closo-dodecaborane-1,2-dithiol (4, 5, 6) and the corresponding metal dimers. In solution (10-4 M) at ambient temperature, the six complexes are stable electron-deficient 16-electron monomers, although the formation of a more electronically stable 18-electron dimer is observed for complex 1 at millimolar concentrations. The six complexes exhibit dramatic differences in reactivity towards electron-donor molecule. The in-vitro anti-inflammatory activities of the 16-e complexes 1 – 6 were investigated on MRC 5-fibroblast and lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. Cells were exposed for 24h to the 16-e complexes 1 – 6 in the concentrations range of 10, 20, 50 and 100uM. After this, drugs were removed and nitric oxide (NO) concentration in the cultured medium was determined by the Griess reaction. Cells were then washed and placed in fresh growth medium for a further 24h as a recovery period. Cell viability was then assessed by MTT assay. Our preliminary data showed that complex 1 – 6 showed some anti-inflammatory effect on both lines, but with slightly differences between them, suggesting that the M-S2C2 scaffold of the electron-deficient complexes is the main structural moiety responsible for such effect. Further studies will focus on the matching these effects with their structures.