Anticancer potential of NSAID-derived tris(pyrazolyl)methane ligands in iron(ii) sandwich complexes

Abstract

Tris(pyrazolyl)methane (tpm), 2,2,2-tris(pyrazolyl)ethanol (tpm^OH) and its esterification derivatives with ibuprofen and flurbiprofen (tpm^IBU and tpm^FLU) were used as ligands to obtain complexes of the type [Fe(tpm^X)₂]Cl₂ (1–4). The tpm^IBU and tpm^FLU ligands and corresponding complexes 3 and 4 were characterized by IR and multinuclear NMR spectroscopy, and the structure of tpm^IBU was elucidated by single crystal X-ray diffraction. Complexes 1–4 were also assessed for their behaviour in aqueous media (solubility in D₂O, octanol/water partition coefficient, stability in physiological-like conditions). The antiproliferative activity of ligands and complexes was determined on A2780, A2780cis and A549 cancer cell lines and the non-cancerous HEK 293T and BJ cell lines. The ligands and complexes were investigated for their ability to inhibit COX-2 (cyclooxygenase) and HNE (4-hydroxynonenal) enzymes. Complexes 3 and 4 exhibited cytotoxicity that may be attributed predominantly to their bioactive fragments, while DNA binding and enhancement of ROS production do not appear to play any significant role.