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

Abstract

In this study, we present the synthesis, characterization and in vitro cytotoxicity of six organometallic [Ru(II)(η⁶-p-cymene)(N,N)Cl]Cl, [Rh(III)(η⁵-C₅Me₅)(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 ¹H 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)(η⁵-C₅Me₅) complexes were characterized by higher water/chloride exchange and pK_a constants compared to their Ru(II)(η⁶-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)(η⁶-p-cymene) complexes interact with human serum albumin via intermolecular forces, while for the Rh(III)(η⁵-C₅Me₅) 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)(η⁶-p-cymene) complexes were found to be the most promising among the tested compounds as they exhibited moderate-to-strong cytotoxic activity (IC₅₀ = 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.