Anti-inflammatory activity of electron-deficient organometallics

Abstract

We report an evaluation of the cytotoxicity of a series of electron-deficient (16-electron) half-sandwich precious metal complexes of ruthenium, osmium and iridium ([Os/Ru(η⁶-p-cymene)(1,2-dicarba-closo-dodecarborane-1,2-dithiolato)] (1/2), [Ir(η⁵-pentamethylcyclopentadiene)(1,2-dicarba-closo-dodecarborane-1,2-dithiolato)] (3), [Os/Ru(η⁶-p-cymene)(benzene-1,2-dithiolato)] (4/5) and [Ir(η⁵-pentamethylcyclopentadiene)(benzene-1,2-dithiolato)] (6)) towards RAW 264.7 murine macrophages and MRC-5 fibroblast cells. Complexes 3 and 6 were found to be non-cytotoxic. The anti-inflammatory activity of 1-6 was evaluated in both cell lines after nitric oxide (NO) production and inflammation response induced by bacterial endotoxin lipopolysaccharide (LPS) as the stimulus. All metal complexes were shown to exhibit dose-dependent inhibitory effects on LPS-induced NO production on both cell lines. Remarkably, the two iridium complexes 3 and 6 trigger a full anti-inflammatory response against LPS-induced NO production, which opens up new avenues for the development of non-cytotoxic anti-inflammatory drug candidates with distinct structures and solution chemistry from that of organic drugs, and as such with potential novel mechanisms of action.

Keywords: anti-inflammatory; carborane; electron-deficient; half-sandwich complexes; mrc-5 fibroblast; nitric oxide (NO).

Figure 1.

Molecular structures of the electron-deficient half-sandwich metal complexes studied in this work.

Figure 2.

Effects of complexes 1–6 on the viability of RAW 264.7 (a,b) and LPS-treated RAW 264.7 (c,d) macrophage cells evaluated by the MTT assay; 24 h (a,c) after treatment by the complexes and with a further 24 h of recovery time (b,d). Detailed data are included in the electronic supplementary material. All statistical analyses refer to the untreated control. *p < 0.05, **p < 0.01, ***p < 0.001.

Figure 3.

Effects of complexes 1–6 on the viability of MRC-5 fibroblasts (a,b) and LPS-treated MRC-5 fibroblast cells (c,d) evaluated by the MTT assay; 24 h (a,c) after treatment by the complexes and with a further 24 h of recovery time (b,d). Detailed data are included in the electronic supplementary material. All statistical analyses refer to the untreated control. *p < 0.05, **p < 0.01, ***p < 0.001.

Figure 4.

Effects of complexes 1–6 on NO production in LPS-induced RAW 264.7 cells. NO production was measured by the Griess reaction assay and expressed as a percentage of the positive control (LPS alone ‘+ −’). The negative control ‘−−’ looks at the NO production for cells untreated with LPS or any complex. Values are the mean + s.d. of at least three independent experiments. Detailed data are included in the electronic supplementary material. All statistical analyses refer to the positive control (LPS alone ‘+ −’). *p < 0.05, **p < 0.01, ***p < 0.001.

Figure 5.

Effects of complexes 1–6 on NO production in LPS-induced MRC-5 fibroblast cells. NO production was measured by the Griess reaction assay and expressed as a percentage of the control (LPS alone ‘+ −’). The negative control ‘− −’ looks at the NO production for cells untreated with LPS or any complex. Values are the mean + s.d. of at least three independent experiments. Detailed data were included in the electronic supplementary material. All statistical analyses refer to the positive control (LPS alone ‘+ −’). *p < 0.05, **p < 0.01, ***p < 0.001.

Figure 6.

UV–visible spectra of complexes 2 and [2-NO] in acetone (10⁻⁴ M, 298 K), and pictures of the corresponding solutions.