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Copper(II) complexes [Cu(H 2 O) 2 (L1)(phen)](ClO 4 ) ( 1 ) and [Cu(H 2 O)(L2)(phen)](ClO 4 ) ( 2 ) (HL1 = naringenin; HL2 = hesperetin) were obtained, in which an anionic flavonoid ligand is attached to the metal center along with 1,10-phenanthroline (phen) as co-ligand. Complexes ( 1 ) and ( 2 ) were assayed for their cytotoxic activity against A549 lung carcinoma and against normal lung fibroblasts (LL-24) and human umbilical vein endothelial cells (HUVEC). We found IC 50  = 16.42 µM ( 1 ) and IC 50  = 5.82 µM ( 2 ) against A549 tumor cells. Complexes ( 1 ) and ( 2 ) exhibited slight specificity, being more cytotoxic against malignant than against non-malignant cells. 1 and 2 induced apoptosis on A549 cells in a mitochondria-independent pathway, and showed antioxidant activity. The antioxidant effect of the complexes could possibly improve their apoptotic action, most likely by a PI3K-independent reduction of autophagy. Complexes ( 1 ) and ( 2 ) interact in vitro with calf thymus DNA by an intercalative binding mode. EPR data indicated that 1 and 2 interact with human serum albumin (HSA) forming mixed ligand species. Graphical abstract

Copper(II) complexes with the first-generation quinolone antibacterial agent norfloxacin containing a nitrogen donor heterocyclic ligand 2,2′-bipyridine (bipy) or 1,10-phenanthroline (phen) were prepared and characterized by IR, EPR spectra, molar conductivity, and elemental analyses. The experimental data suggest that norfloxacin was coordinated to copper(II) through the carboxylato and ketone oxygen atoms. The interaction of the copper(II) complexes with bovine serum albumin (BSA) and human serum albumin (HSA) was investigated using fluorescence quenching of the tryptophan residues and copper(II) EPR spectroscopy. The results of fluorescence titration revealed that copper(II) complexes have a moderate ability to quench the intrinsic fluorescence of the albumins through a static quenching mechanism. EPR experiments showed that BSA and HSA Cu(II) sites compete with NOR for Cu(II)-bipy and Cu(II)-phen to form protein mixed-ligand complexes. Copper(II) complexes, together with the corresponding ligands, were evaluated for their trypanocidal activity in vitro against Trypanosoma cruzi, the causative agent of Chagas disease. The tests performed using bloodstream trypomastigotes showed that the Cu(II)-N-donor precursors and the metal complexes were more active than the free fluoroquinolone.

Zn(II) complexes with norfloxacin (NOR) in the absence or in the presence of 1,10-phenanthroline (phen) were obtained and characterized. In both complexes, the ligand NOR was coordinated through a keto and a carboxyl oxygen. Tetrahedral and octahedral geometries were proposed for [ZnCl 2 (NOR)]·H 2 O ( 1 ) and [ZnCl 2 (NOR)(phen)]·2H 2 O ( 2 ), respectively. Since the biological activity of the chemicals depends on the pH value, pH titrations of the Zn(II) complexes were performed. UV spectroscopic studies of the interaction of the complexes with calf-thymus DNA (CT DNA) have suggested that they can bind to CT DNA with moderate affinity in an intercalative mode. The interactions between the Zn(II) complexes and bovine serum albumin (BSA) were investigated by steady-state and time-resolved fluorescence spectroscopy at pH 7.4. The experimental data showed static quenching of BSA fluorescence, indicating that both complexes bind to BSA. A modified Stern–Volmer plot for the quenching by complex 2 demonstrated preferential binding near one of the two tryptophan residues of BSA. The binding constants obtained ( K b ) showed that BSA had a two orders of magnitude higher affinity for complex 2 than for 1 . The results also showed that the affinity of both complexes for BSA was much higher than for DNA. This preferential interaction with protein sites could be important to their biological mechanisms of action. The analysis in vitro of the Zn(II) complexes and corresponding ligand were assayed against Trypanosoma cruzi , the causative agent of Chagas disease and the data showed that complex 2 was the most active against bloodstream trypomastigotes.

Copper(II) complexes of fluoroquinolone antibacterial agents levofloxacin (LEV) and sparfloxacin (SPAR), containing or not a nitrogen donor heterocyclic ligand, 2,2′-bipyridine (bipy) or 1,10-phenathroline (phen), were prepared and characterized. The complexes are of the type [CuCl 2 (H 2 O)(L)], [CuCl(bipy)(L)]Cl and [CuCl 2 (phen)(L)], where L = LEV or SPAR. The data suggest that LEV and SPAR act as zwitterionic bidentade ligands coordinated to Cu(II) through the carboxylate and ketone oxygen atoms. The electron paramagnetic resonance spectra of the [CuCl(bipy)(L)]Cl and [CuCl 2 (phen)(L)] complexes (L = LEV and SPAR) in aqueous and DMSO solutions indicate mixture of mononuclear and binuclear forms. The Cu(II) complexes, together with the corresponding ligands, were evaluated for their trypanocidal activity in vitro against Trypanosoma cruzi , the causative agent of Chagas disease. The assays performed against bloodstream trypomastigotes showed that all complexes were more active than their corresponding ligands. Complexes [CuCl 2 (phen)(LEV)] and [CuCl 2 (phen)(SPAR)] were revealed, among all studied compounds, to be the most active with IC 50  = 1.6 and 4.7 μM, respectively, both presenting a superior effect than benznidazole. The interactions of fluoroquinolones and their Cu(II) complexes with calf-thymus DNA were investigated. These compounds showed binding properties towards DNA, with moderated binding constants values, suggesting that this structure may represent a parasite target.

Formation of gold(III) complexes with the synthetic antibiotic norfloxacin (NF) was investigated in aqueous solution at pH 4.0, 7.5 and 10.6, with the ligand in cationic, zwitterionic and anionic forms, respectively. UV-Visible spectroscopy, steady state and time-resolved fluorometry were used to characterize the complexes. Binding sites, association constants and fluorescence lifetimes of the complexes were obtained. Au3+ binding to zwitterionic NF produced a fluorescence decrease and a small red shift. Fluorescence changes as a function of Au3+ concentration were fitted using a one-site binding model and the association constant was obtained, \\( K_b^zw = 1.7 10^5\\;M^1 \\). The association of Au3+ with cationic NF was much weaker, the obtained binding constant being \\( K_b^cat = 2.4 10^3\\;M^1 \\). The Au3+ binding site for these species involves the carboxyl group, in agreement with a much stronger association of the cation with the carboxylate anion than with the neutral acid. Association of Au3+ with nonfluorescent anionic NF presented a clear evidence of two binding sites. The highest affinity site is the unprotonated piperazinyl group with \\( K_b^pip 5 10^7\\;M^ - 1 \\), and the low affinity site includes the carboxylate anion. The results point out to important pH dependent differences in complex formation between transition metal ions and fluoroquinolones, leading to different binding sites and association constants that change by several orders of magnitude.

This work reports the results of ultraviolet irradiation on the interaction of the phototoxic antipsychotic drug chlorpromazine (CPZ) with the sodium pump Na+, K+‐ATPase. The study was performed by monitoring the fluorescence modifications of CPZ itself and of the specific probe anthroylouabain (AO). CPZ association with Na+, K+‐ATPase was found to modify the kinetics of CPZ‐photodegradation. It was demonstrated that UV irradiation produces a stable fluorescent photoproduct of CPZ covalently bound to Na+, K+‐ATPase. The fluorescent probe AO, which specifically binds to the extracellular ouabain site of the pump, was used to localize the CPZ binding site. UV‐irradiation of AO‐labeled Na+, K+‐ATPase treated with CPZ at concentration about 20 μM produced dose‐dependent modifications of the AO fluorescence, e.g. increased quantum yield and blue shift. The results demonstrated that CPZ binds near the ouabain site. The photo‐induced reaction of CPZ with AO‐labeled Na+, K+‐ATPase protected the ouabain site from the aqueous environment. It was also found that UV irradiation of CPZ‐treated enzyme obstructs the binding of AO, which suggested occlusion of the ouabain site. This effect can be evaluated for a potential use of CPZ in photochemotherapy.