Anticancer Ruthenium(η⁶‑<i>p</i>‑cymene) Complexes of Nonsteroidal Anti-inflammatory Drug Derivatives

Abstract

Oxicams are a versatile family of heterocyclic compounds, and the two representatives meloxicam and piroxicam are widely used drugs for the treatment of a variety of inflammatory and rheumatic diseases in humans. As cancer-associated inflammation is known to occur in carcinogenesis, we aimed to combine compounds carrying bioactive oxicam moieties with ruthenium­(arene) fragments, known for anticancer activity. Ru^II(arene) complexes with methyl ester derivatives of the oxicam scaffold were prepared and characterized by standard methods and crystallographically. The organoruthenium compounds formed from Ru^II(η⁶-<i>p</i>-cymene) chlorido moieties and oxicam-based ligands were subjected to bioanalytical investigations to establish their physicochemical properties with regard to stability in DMSO and water as well as reactivity toward the amino acids l-histidine (His), l-methionine (Met), and l-cysteine (Cys) and the DNA model compound guanosine 5′-monophosphate (5′-GMP). The compounds hydrolyzed rapidly in water to give the respective aqua complexes, formed amino acid complexes with Met and His, but decompose with Cys, while interaction with 5′-GMP was through its phosphate residue. The anticancer activity of the complexes against the colon carcinoma HCT116 and breast cancer MDA MB 231 cancer cell lines was established using an <i>in vitro</i> assay. The cytotoxicity was found strongly dependent on the lipophilicity of the compound, as was shown through correlation with log<i> k</i>_w and clog<i> P</i> values of the ligands. The most lipophilic compound [chlorido­(methyl 4-oxido-2-benzyl-2<i>H</i>-1,2-benzothiazine-3-carboxylate-1,1-dioxide)­(η⁶-<i>p</i>-cymene)­ruthenium­(II)] was the most active in the cell assays, with an IC₅₀ of 80 μM in HCT116 cells