Novel family of [RuCp(N,N)(P)]⁺ compounds with simultaneous anticancer and antibacterial activity: Biological evaluation and solution chemistry studies

A family of ten novel ruthenium(II)-cyclopentadienyl organometallics of general formula [Ru(η⁵-C₅H₅)(N,N)(PPh₂(C₆H₄COOR)][CF₃SO₃] (1-10) in which (N,N) = 4,4'-R'-2,2'-bipyridyl (R = -H or -CH₂CH₂OH; R' = -H, -CH₃, -OCH₃, -CH₂OH, and -CH₂-biotin) was prepared from [Ru(η⁵-C₅H₅)(PPh₂(C₆H₄COOH))₂Cl]. All compounds were fully characterized by means of several spectroscopic and analytical techniques, and the molecular structures of [Ru(η⁵-C₅H₅)(PPh₂(C₆H₄COOH))₂Cl], 1, 3 and 4 have been additionally studied by single-crystal X-ray diffraction. The anticancer activity of all compounds was evaluated in sensitive and multidrug-resistant counterpart cell lines from human colorectal cancer (Colo 205 and Colo 320) and non-small cell lung cancer NSCLC (A549, NCI-H460 versus NCI-H460/R) as well. Notably, compounds 6 and 7 (R CH₂CH₂OH and (N,N) = bipy or Me₂bipy, respectively) showed antiproliferative effect against both cell lines with high intrinsic selectivity towards cancer cells. The antibacterial activity of all compounds was also evaluated against both Gram negative and Gram positive strains, and some compounds in the series showed potent antibacterial activity against Staphylococcus aureus strains, including the methicillin-resistant MRSA strains. Solution speciation studies revealed that the complexes bearing the PPh₂(C₆H₄COO^-) ligand are neutral at physiological pH (7.4) in contrast with their ethylene glycol derivatives that have a permanent positive charge. While all compounds are lipophilic, the difference in the distribution coefficient for neutral and charged complexes is around one order of magnitude. Complexes 6 and 7 exhibited excellent biological activity and were selected for further studies. Spectrofluorometric methods were used to investigate their interaction with biomolecules such as human serum albumin (HSA) and calf thymus DNA (ct-DNA). For these complexes, binding site II of HSA is a possible binding pocket through non-covalent interactions. The release of ethidium from the DNA adduct by the charged complexes proves their interaction with DNA in contrast to the neutral ones. In conclusion, Ru(II)-cyclopentadienyl complexes with 2,2'-bipyridyl-derivatives and an ethylene glycol moiety tethered to the phenylphosphane co-ligand are very promising from a therapeutic perspective, in particular complexes 6 and 7 that display remarkable antibacterial activity with a high anti-proliferative effect against colon and non-small cell lung cancers, both clinically challenging neoplasias in need of effective solutions.