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

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 ]Cl 2 ( 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 D 2 O, 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. Flurbiprofen and ibuprofen have been tethered to the skeleton of tris(pyrazolyl)methane, the resulting iron(II) complexes displaying antiproliferative activity and enzyme inhibition capacity largely influenced by the bioactive fragment.