Organometallic Ru(II), Rh(III) and Re(I) complexes of sterane-based bidentate ligands: synthesis, solution speciation, interaction with biomolecules and anticancer activity.

In this study, we present the synthesis, characterization and in vitro cytotoxicity of six organometallic [Ru(II)(η 6 - p -cymene)( N , N )Cl]Cl, [Rh(III)(η 5 -C 5 Me 5 )( N , N )Cl]Cl and [Re(I)(CO) 3 ( N , N )Cl] complexes, in which the ( N , N ) ligands are sterane-based 2,2'-bipyridine derivatives (4-Me-bpy-St-OH, 4-Ph-bpy-St-OH). The solution chemical behavior of the ligands and the complexes was explored by UV-visible spectrophotometry and 1 H NMR spectroscopy. The ligands and their Re(I) complexes are neutral at pH = 7.40; this contributes to their highly lipophilic character (log  D 7.40 > +3). The Ru(II) and Rh(III) half-sandwich complexes are much more hydrophilic, and this property is greatly affected by the actual chloride ion content of the medium. The half-sandwich Ru and Rh complexes are highly stable in 30% (v/v) DMSO/water (<5% dissociation at pH = 7.40); this is further increased in water. The Rh(III)(η 5 -C 5 Me 5 ) complexes were characterized by higher water/chloride exchange and p K a constants compared to their Ru(II)(η 6 - p -cymene) counterparts. The Re(I)(CO) 3 complexes are also stable in solution over a wide pH range (2-12) without the release of the bidentate ligand; only the chlorido co-ligand can be replaced with OH - at higher pH values. A comprehensive discussion of the binding affinity of the half-sandwich Ru(II) and Rh(III) complexes toward human serum albumin and calf-thymus DNA is also provided. The Ru(II)(η 6 - p -cymene) complexes interact with human serum albumin via intermolecular forces, while for the Rh(III)(η 5 -C 5 Me 5 ) complexes the coordinative binding mode is suggested as well. They are also able to interact with calf-thymus DNA, most likely via the coordination of the guanine nitrogen. The Ru(II)(η 6 - p -cymene) complexes were found to be the most promising among the tested compounds as they exhibited moderate-to-strong cytotoxic activity (IC 50 = 3-11 μM) in LNCaP as well as in PC3 prostate cells in an androgen receptor-independent manner. They were also significantly cytotoxic in breast and colon adenocarcinoma cancer cell lines and showed good selectivity for cancer cells.