Ruthenium(II) arene NSAID complexes: inhibition of cyclooxygenase and antiproliferative activity against cancer cell lines

Non-steroidal anti-inflammatory drugs (NSAIDs) are a group of molecules which have been found to be active against cancer cells with chemopreventive properties by targeting cyclooxygenase (COX-1 and COX-2) and lipoxygenase (LOX), commonly upregulated (particularly COX-2) in malignant tumors. Arene ruthenium(II) complexes with a pseudo-octahedral coordination environment containing different ancillary ligands have shown remarkable activity against primary and metastatic tumors as reported earlier. This work describes the synthesis of four novel ruthenium(II)-arene complexes viz. [Ru(eta(6)-p-cymene)(nap) Cl] 1 [Hnap = naproxen or (S)-2-(6-methoxy-2-naphthyl) propionic acid], [Ru(eta(6)-p-cymene)(diclo) Cl] 2 [Hdiclo = diclofenac or 2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, [Ru(eta(6)-p-cymene)(ibu) Cl] 3 [Hibu = ibuprofen or 2-(4-isobutylphenyl) propanoic acid] and [Ru(eta(6)-p-cymene)(asp) Cl] 4 [Hasp = aspirin or 2-acetoxy benzoic acid] using different NSAIDs as chelating ligands. Complexes 1-3 have shown promising antiproliferative activity against three different cell lines with GI(50) (concentration of drug causing 50% inhibition of cell growth) values comparable to adriamycin. At the concentration of 50 mu M, complex 3 is more effective in the inhibition of cyclooxygenase and lipooxygenase enzymes, followed by complex 2 and complex 1 in comparison to their respective free NSAID ligands indicating a possible correlation between the inhibition of COX and/or LOX and anticancer properties. Molecular docking studies with COX-2 reveal that complexes 1 and 2 having naproxen and diclofenac ligands exhibit stronger interactions with COX-2 than their respective free NSAIDs and these results are in good agreement with their relative experimentally observed COX inhibition as well as anti-proliferative activities.