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

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(H2O)2], [Co(tolf)2(H2O)2], [Ni(tolf2(H2O)2], [Cu(tolf)2(H2O)]2, and [Zn(tolf)2(H2O)] 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, β-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(H2O)] 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(H2O)2] and [Cu(tolf)2(H2O)]2 have shown selectivity against T24 cell line. The IC50 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.