Unexpected solution behaviour of ester-functionalized half-sandwich Ru(ii) and Ir(iii) complexes

Abstract

Complexes [Ru(η⁶-pcym)(bpy^dca)Cl]PF₆ (Ru^dca) and [Ir(η⁵-Cp*)(bpy^dca)Cl]PF₆ (Ir^dca) were developed as model compounds for the investigation of multi-targeted ester-functionalized half-sandwich ruthenium(II) and iridium(III) complexes; pcym = 1-methyl-4-(propan-2-yl)benzene (p-cymene), bpy^dca = 2,2′-bipyridine-4,4′-diyldimethanediyl bis(dichloroacetate), Cp* = pentamethylcyclopentadienyl. Aiming to understand the in-solution behaviour of these first-in-class complexes containing the pyruvate dehydrogenase kinase inhibitor dichloroacetate (dca) as the terminal bioactive substituent, several experiments were performed under aqueous conditions for Ru^dca and Ir^dca, as well as for compounds [Ru(η⁶-pcym)(bpy^OH)Cl]PF₆ (Ru^OH) and [Ir(η⁵-Cp*)(bpy^OH)Cl]PF₆ (Ir^OH), and acetyl analogues [Ru(η⁶-pcym)(bpy^ac)Cl]PF₆ (Ru^ac) and [Ir(η⁵-Cp*)(bpy^ac)Cl]PF₆ (Ir^ac) bearing a different (biologically inactive) terminal substituent; bpy^OH = 2,2′-bipyridine-4,4′-diyldimethanol, bpy^ac = 2,2′-bipyridine-4,4′-diyldimethanediyl diacetate. The experiments were also conducted in the presence of porcine liver esterase (PLE). All the six complexes were characterized by relevant techniques (e.g., NMR and mass spectrometry), including a single-crystal X-ray analysis of complexes Ru^dca, Ru^ac, Ru^OH and Ir^OH. Although designed as model compounds, Ru^dca, Ir^dca, Ru^OH and Ir^OH were also screened for their antiproliferative activity in four human cancer cell lines (HCT116 colon carcinoma, MDA-MB-231 and MCF-7 breast adenocarcinomas, DU145 prostate carcinoma), where the tested complexes did not show any effect (IC₅₀ > 100 μM).