Physicochemical Studies and Anticancer Potency of Ruthenium η⁶-<i>p</i>-Cymene Complexes Containing Antibacterial Quinolones

With the aim of exploring the anticancer properties of organometallic compounds with bioactive ligands, Ru(arene) compounds of the antibacterial quinolones nalidixic acid (<b>2</b>) and cinoxacin (<b>3</b>) were synthesized, and their physicochemical properties were compared to those of chlorido(η⁶-<i>p</i>-cymene)(ofloxacinato-κ²<i>O</i>,<i>O</i>)ruthenium(II) (<b>1</b>). All compounds undergo a rapid ligand exchange reaction from chlorido to aqua species. <b>2</b> and <b>3</b> are significantly more stable than <b>1</b> and undergo minor conversion to an unreactive [(cym)Ru(μ-OH)₃Ru(cym)]⁺ species (cym = η⁶-<i>p</i>-cymene). In the presence of human serum albumin <b>1</b>−<b>3</b> form adducts with this transport protein within 20 min of incubation. With guanosine 5′-monophosphate (5′-GMP; as a simple model for reactions with DNA) very rapid reactions yielding adducts via its N7 atom were observed, illustrating that DNA is a possible target for this compound class. A moderate capacity of inhibiting tumor cell proliferation in vitro was observed for <b>1</b> in CH1 ovarian cancer cells, whereas <b>2</b> and <b>3</b> turned out to be inactive

Structure–Activity Relationships of Targeted Ru^II(η⁶‑<i>p</i>‑Cymene) Anticancer Complexes with Flavonol-Derived Ligands

Ru^II(arene) complexes have been shown to be promising anticancer agents, capable of overcoming major drawbacks of currently used chemotherapeutics. We have synthesized Ru^II(η⁶-arene) compounds carrying bioactive flavonol ligands with the aim to obtain multitargeted anticancer agents. To validate this concept, studies on the mode of action of the complexes were conducted which indicated that they form covalent bonds to DNA, have only minor impact on the cell cycle, but inhibit CDK2 and topoisomerase IIα in vitro. The cytotoxic activity was determined in human cancer cell lines, resulting in very low IC₅₀ values as compared to other Ru^II(arene) complexes and showing a structure–activity relationship dependent on the substitution pattern of the flavonol ligand. Furthermore, the inhibition of cell growth correlates well with the topoisomerase inhibitory activity. Compared to the flavonol ligands, the Ru^II(η⁶-<i>p</i>-cymene) complexes are more potent antiproliferative agents, which can be explained by potential multitargeted properties