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

Abstract

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(η-p-cymene)(nap)Cl] 1 [Hnap = naproxen or (S)-2-(6-methoxy-2-naphthyl)propionic acid], [Ru(η-p-cymene)(diclo)Cl] 2 [Hdiclo = diclofenac or 2-[(2,6-dichlorophenyl)amino] benzeneacetic acid, [Ru(η-p-cymene)(ibu)Cl] 3 [Hibu = ibuprofen or 2-(4-isobutylphenyl)propanoic acid] and [Ru(η-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 (concentration of drug causing 50% inhibition of cell growth) values comparable to adriamycin. At the concentration of 50 μM, 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.

Rationally Designed Ruthenium Complexes for Breast Cancer Therapy

“…It is worth mentioning that the potential COX inhibition activity of the compounds discussed above was not studied. More recently, Mukhopadhyay et al (2018) reported a series of ruthenium(II) cymene complexes bearing different NSAID ligands, (13) (Figure 3), including diclofenac and ibuprofen, but also naproxen (Npx) and aspirin (Asp) [82]. Except for the Ru-Asp complex, which was found inactive against MCF7 cells, all complexes displayed a lower IC 50 value (<0.1 µM) than their corresponding free NSAID (>80 µM) in this cell line.…”

“Half-Sandwich”/RuII Anticancer Complexes Containing Triphenylphosphine and p-Substituted Benzoic Acids

“…Thus, the main problem of these kinds of Ru II /η 6 -arene/carboxylate complexes can be their low stability in coordinating solvents or physiological medium, limiting their biological application. 37,38 Benzoic acid and its analogs belong to an important class of ligands, displaying a structural diversity, allowing them to access the ortho, meta and para positions with a wide possibility of substitution with many organic functions. Due to the promising chemical and biological results obtained with the Ru II /η 6 -arene-based complexes, this paper reports on the reactivity of p-substituted benzoic acid derivatives with Ru II /η 6 -arene/triphenylphosphine complexes with general formula [Ru(η 6…”

Antiproliferative Activity of Gold(I) N‐Heterocyclic Carbene and Triphenylphosphine Complexes with Ibuprofen Derivatives as Effective Enzyme Inhibitors

“…There are reports of silver(I), gold(I), and zinc (II) complexes with ibuprofen for antibacterial activities. Also, a platinum (II)/(IV), Ru (II), Cu (II) complexes with ibuprofen have been reported as anticancer drugs . Recently, we also have reported the antioxidant activity of copper (II) complexes of ibuprofen amide‐phenanthroline and cyclometalated ruthenium (II) complex containing ibuprofen for inhibition of cyclooxygenase and in vitro cytotoxicity activities .…”