Anti‐Inflammatory, Antiproliferative, and Radical‐Scavenging Activities of Tolfenamic Acid and Its Metal Complexes

Abstract

Some new complexes of tolfenamic acid (=2-[(2-methyl-3-chlorophenyl)amino]benzoic acid; Htolf) with potentially interesting biological activities are described. The complexes [Mn(tolf)(2)(H(2)O)(2)], [Co(tolf)(2)(H(2)O)(2)], [Ni(tolf(2)(H(2)O)(2)], [Cu(tolf)(2)(H(2)O)](2), and [Zn(tolf)(2)(H(2)O)] were prepared by the reaction of tolfenamic acid, a potent anti-inflammatory drug, with metal salts. The radical-scavenging activities of the complexes were evaluated using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical-scavenging assay. Their ability to inhibit soybean lipoxygenase, beta-glucuronidase, and trypsin-induced proteolysis was studied. Their inhibitory effects on rat paw edema induced by carrageenin was studied and compared with those of tolfenamic acid. The complex [Zn(tolf)(2)(H(2)O)] exhibited the strongest in vivo inhibitory effect at 0.1 mm/kg Body Weight (BW; 93.0+/-0.9%), superior than the inhibition induced by tolfenamic acid at the same molar dose (76.0+/-0.9%). Tolfenamic acid and its metal complexes have been evaluated for antiproliferative activity in vitro against the cells of three human cancer cell lines, MCF-7 (breast cancer cell line), T24 (bladder cancer cell line), and A-549 (non-small cell lung carcinoma), and a mouse fibroblast L-929 cell line. The complexes [Mn(tolf)(2)(H(2)O)(2)] and [Cu(tolf)(2)(H(2)O)](2) have shown selectivity against T24 cell line. The IC(50) values of these two complexes against T24 cancer cell lines are in a micromolar range similar or better to that of the antitumor drug cisplatin.

The synthesis and characterization of a series of cobalt(II) β-ketoaminato complexes and their cytotoxic activity towards human tumor cell lines

“…We observed similar cell-type specific activity of cobalt complexes, with notable effect on human prostate cancer and monocytic leukemia cells and weak or no effect on neuroblastoma, astrocytoma or hepatocellular carcinoma cells. Additional examples of cell type specificity were described for the complex of cobalt with mefenamic acid [37]; however, the EC 50 values towards human MCF-7 breast cancer (94 μM), T-24 bladder cancer (27 μM), and A-549 non-small cell lung carcinoma (116 μM) were generally higher than those observed in our study. Cell type specific cytotoxic effects have been observed not only for Co(II) complexes but also for compounds containing a number or other metals, including Cu(II), Zn(II), Mn(II), Mo(VI), Ni(II), as well as Co(III) [37][38][39][40].…”

Cellular and Organismal Toxicity of the Anti-Cancer Small Molecule, Tolfenamic Acid: a Pre-Clinical Evaluation

“…All these results showed limited cytotoxicity and GI effects. TA also has an excellent therapeutic index in humans [51,52]. Relatively low GI toxicity could be an added advantage for TA when compared to other NSAIDs, apart from its specificity in targeting Sp transcription factors and survivin.…”

Preparation and pharmacochemical evaluation of mixed ligand copper(II) complexes with triethanolamine and thiophenyl-2 saturated carboxylic acids

“…Ref. [48], it was found to interact very lowly with DPPH (4.6% RA) while no action was found for CuCl 2 2H 2 O to the rest of the assays under the experimental conditions. 2.4.1.…”