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, [Cu3(h2imi−)2Cl4], show that coordination of hydrazones to Cu(II) occurs by tridentate modes of the type κ3(O,N,N′) as well as bidentate modes of the type κ2(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 GI50 values. Complexes 3 (GI50 = 1.14 μM, SI = 4.52) and 4 (GI50 = 2.72 μM, SI = 6.06) were more active and selective against 786-0 cell lines than doxorubicin (GI50 = 85.0 μM, SI = 5·10−3). Complex 1A presented high selectivity indexes against glioma (U251, GI50 = 2.53 μM, SI = 60.9) and multiple drugs resistance ovarian (NCI/ADR-RES GI50 = 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.