Polynuclear copper(II) complexes with nalidixic acid hydrazones: Antiproliferative activity and selectivity assessment over a panel of tumor cells

Abstract Polynuclear copper(II) complexes with nalidixic acid hydrazones derivatives containing 2-imidazolyl (h2imi, complexes 1A and 1B ), 4-imidazolyl (h4imi, complexes 2A and 2B ), salicyl (hsali, complex 3 ) and 1H-pyrrolyl (hpyrr, complex 4 ) units were synthesized and characterized by chemical and spectroscopic methods. Crystallographic studies of complex 1B , [Cu 3 (h2imi − ) 2 Cl 4 ], show that coordination of hydrazones to Cu(II) occurs by tridentate modes of the type κ 3 (O,N,N′) as well as bidentate modes of the type κ 2 (O′,N″). For complexes 2A and 4 , EPR data are compatible with a trinuclear structure, based on an antiferromagnetic coupling between copper centers that is stronger at low temperature. Complexes 1A , 2A , 3 and 4 had their antiproliferative activities evaluated in vitro against a panel of tumor cells by determination of GI 50 values. Complexes 3 (GI 50  = 1.14 μM, SI = 4.52) and 4 (GI 50  = 2.72 μM, SI = 6.06) were more active and selective against 786-0 cell lines than doxorubicin (GI 50  = 85.0 μM, SI = 5·10 −3 ). Complex 1A presented high selectivity indexes against glioma (U251, GI 50  = 2.53 μM, SI = 60.9) and multiple drugs resistance ovarian (NCI/ADR-RES GI 50  = 1.69 μM, SI = 91.4) cell lines when compared to doxorubicin and cisplatin. DNA gel electrophoresis (pIRES DNA) and cell-cycle arrest (NCI/ADR-RES cell line) assays were performed with complex 1A . The obtained results suggest that the mechanism of action of complex 1A does not involve DNA interaction and complex 1A seems to be a cell cycle non-specific drug.