Nonsteroidal Anti-inflammatoryOrganometallic Anticancer Compounds

Compounds that combine metal-based drugs with covalently linked targeted organic agents have been shown, in some instances, to exhibit superior anticancer properties compared to the individual counterparts. Within this framework, we prepared a series of organometallic ruthenium­(II)- and osmium­(II)-p-cymene complexes modified with the nonsteroidal anti-inflammatory drugs (NSAIDs) indomethacin and diclofenac. The NSAIDs are attached to the organometallic moieties via monodentate (pyridine/phosphine) or bidentate (bipyridine) ligands, affording piano-stool Ru­(II) and Os­(II) arene complexes of general formula [M­(η6-p-cymene)­Cl2(N)], where N is a pyridine-based ligand, {2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)­acetoxy)­ethyl-3-(pyridin-3-yl)­propanoate} or {2-(2-(2-((2,6-dichlorophenyl)­amino)­phenyl)­acetoxy)­ethyl-3-(pyridin-3-yl)­propanoate}, [M­(η6-p-cymene)­Cl2(P)], where P is a phosphine ligand, {2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)­acetoxy)­ethyl-4-(diphenylphosphanyl)­benzoate} or {2-(2-(2-((2,6-dichlorophenyl)­amino)­phenyl)­acetoxy)­ethyl-4-(diphenylphosphanyl)­benzoate, and [M­(η6-p-cymene)­Cl­(N,N′)]­[Cl], where N,N′ is a bipyridine-based ligand, (4′-methyl-[2,2′-bipyridin]-4-yl)­methyl-2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)­acetate), (4′-methyl-[2,2′-bipyridin]-4-yl)­methyl-2-(2-((2,6-dichlorophenyl)­amino)­phenyl)­acetate), (bis­(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)­acetoxy)­ethyl)­[2,2′-bipyridine]-5,5′-dicarboxylate), or (bis­(2-(2-(2-((2,6-dichlorophenyl)­amino)­phenyl)­acetoxy)­ethyl)­[2,2′-bipyridine]-5,5′-dicarboxylate). The antiproliferative properties of the complexes were assessed in human ovarian cancer cells (A2780 and A2780cisR, the latter being resistant to cisplatin) and nontumorigenic human embryonic kidney (HEK-293) cells. Some of the complexes are considerably more cytotoxic than the original drugs and also display significant cancer cell selectivity.