Electroporation Enhances the Anticancer Effects of Novel Cu(II) and Fe(II) Complexes in Chemotherapy-Resistant Glioblastoma Cancer Cells.

Schiff base ligand (L) was obtained by condensation reaction between 4-aminopyrimidin-2(1H)-one (cytosine) with 2-hydroxybenzaldehyde. The synthesized Schiff base was used for complexation with Cu(II) and Fe(II) ions used by a molar (2 : 1 mmol ration) in methanol solvent. The structural features of ligand, Cu(II), and Fe(II) metal complexes were determined by standard spectroscopic methods (FT-IR, elemental analysis, proton and carbon NMR spectra, UV/VIS, and mass spectroscopy, magnetic susceptibility, thermal analysis, and powder X-ray diffraction). The synthesized compounds (Schiff base and its metal complexes) were screened in terms of their anti-proliferative activities in U118 and T98G human glioblastoma cell lines alone or in combination with electroporation (EP). Moreover, the human HDF (human dermal fibroblast) cell lines was used to check the bio-compatibility of the compounds. Anti-proliferative activities of all compounds were ascertained using an MTT assay. The complexes exhibited a good anti-proliferative effect on U118 and T98G glioblastoma cell lines. In addition, these compounds had a negligible cytotoxic effect on the fibroblast HDF cell lines. The use of compounds in combination with EP significantly decreased the IC50 values compared to the use of compounds alone (p<0.05). These results show that newly synthesized Cu(II) and Fe(II) complexes can be developed for use in the treatment of chemotherapy-resistant U118 and T98G glioblastoma cells and that treatment with lower doses can be provided when used in combination with EP.

Synthesis, characterization, antioxidant and anticancer activities of a new Schiff base and its M(II) complexes derived from 5-fluorouracil.

In this study, Schiff base ligand was obtained from the condensation reaction of benzene-1,2-diamine and 5-fluoropyrimidine-2,4(1H,3H)-dione (5-FU). Metal(II) complexes were synthesized with Fe(II), Co(II) and Ni(II) chloride salts. The synthesized ligand and metal complexes were characterized by FT-IR, UV-vis, 1H-13C NMR, elemental analyses, mass spectroscopy, magnetic moments, molar conductivity and thermogravimetric analysis studies. With the help of different techniques reveal Fe(II), Co(II) and Ni(II) complexes have exhibited tetrahedral and octahedral geometry. Ligand acted as bidentate and it binds metal(II) ions through deprotonated-NH, imine-N atom and carbonyl-O atom, respectively. DPPH, ABTS, FRAP, CUPRAC and total antioxidant activity methods were used to determine the antioxidant properties of ligand and metal complexes. According to the results, the synthesized compounds showed very high antioxidant activity compared to 5-FU. The cytotoxicities of the synthesized compounds were performed on MCF-7 (human breast cancer) and L-929 (fibroblast) cell lines using the MTT assay. In addition, the effect of electroporation (EP) on the cytotoxicity of the compounds was investigated. Our results demonstrated that novel Co(II) and Ni(II) complexes show potential as new anticancer agents and ECT may be a viable treatment option for breast cancer.

Synthesis, characterization, antiproliferative of pyrimidine based ligand and its Ni(II) and Pd(II) complexes and effectiveness of electroporation.

In the study, a new Schiff base (ligand) was obtained using 4-aminopyrimidine-2(1H)-one, the starting material, and 2,3,4-trimethoxy benzaldehyde. Ni(II) and Pd(II) complexes were obtained from the reaction of the ligand and NiCl2·6H2O, PdCl2(CH3CN)2 (1:1 ratio). These compounds were characterized using the elemental and mass analysis, 1H, 13C-NMR, FT-IR, UV-Vis, magnetic susceptibility, thermal analysis, and the X-ray diffraction analyses. The antiproliferative activities of the synthesized ligand, Ni(II) and Pd(II) complexes were identified on the HepG2 (human liver cancer cells) cell line and their biocompatibility was tested on the L-929 (fibroblast cells) cell line by the MTT analysis method. Furthermore, the effects of electroporation (EP) on the cytotoxic activities of synthesized compounds were investigated in HepG2 cancer cells. According to the MTT findings of the study, the ligand did not exhibit an antiproliferative activity while its Ni(II) and Pd(II) complexes exhibited an antiproliferative activity. Moreover, it was observed that the antiproliferative activity of the Pd(II) complex was stronger than that of the Ni(II) complex. The combined application of EP + compounds is much more effective than the usage of the compounds alone in the treatment of HepG2 cancer cells. The EP increased the cytotoxicity of the Ni(II) and Pd(II) complexes by 1.66, and 2.54 times, respectively. It was concluded that Ni(II) and Pd(II) complexes may contribute as potential anti-cancer agents for the treatment of hepatocellular carcinoma and yield promising results in the case of being used in ECT.Communicated by Ramaswamy H. Sarma.

Some metal chelates with Schiff base ligand: synthesis, structure elucidation, thermal behavior, XRD evaluation, antioxidant activity, enzyme inhibition, and molecular docking studies.

Schiff bases are well-known compounds for having significant biological properties. In this study, a new Schiff base ligand and its metal complexes were synthesized, and their antioxidant and enzyme inhibitory activities were evaluated. The new Schiff base ligand was synthesized with the condensation reaction of 6-tert-butyl 3-ethyl 2-amino-4,5-dihydrothieno[2,3-c]pyridine-3,6(7H)-dicarboxylate and 2-hydroxybenzaldehyde compounds. Fe(II), Co(II), and Ni(II) metal complexes of the novel Schiff base ligand were synthesized and characterized. The purity and molecular formula of the synthesized compounds were identified with elemental analysis, infrared, ultraviolet-visible, mass spectrophotometry, powder XRD, magnetic and thermal measurements. The Schiff base acted as a three dentate chelate. The analytical and spectroscopic data suggested an octahedral geometry for the complexes. The in vitro antioxidant method studies elucidated a more effective antioxidant character of the Schiff base ligand than its metal complexes but a less effective antioxidant potential than the standard antioxidant compounds. The enzyme inhibition potentials of the synthesized compounds for AChE, BChE, and GST enzymes were determined by in vitro enzyme activity methods. The Schiff base ligand was discovered to be the best inhibitor for the AChE and BChE with the values of 7.13 ± 0.84 µM and 5.75 ± 1.03 µM Ki, respectively. Moreover, the Fe(II) complex displayed the best Ki value as 9.37 ± 1.06 µM for the GST enzyme. Finally, molecular docking studies were carried out to see the structural interactions of the compounds. The metal complexes demonstrated better binding affinities with the AChE, BChE, and GST enzymes than the Schiff base ligand. This study identified a potential Schiff base molecule against both AChE and BChE targets to further investigate for in vivo and safety evaluation.

Effects of electroporation on anticancer activity of 5-FU and newly synthesized zinc(II) complex in chemotherapy-resistance human brain tumor cells.

Zn(II) complex of Schiff base derived from the condensation of 4-aminopyrimidine-2(1H)-one with salicylaldehyde was prepared and characterized by various physico-chemical and spectral methods for structure determination. The cytotoxic activity of the Zn(II) complex was investigated in comparison with 5-fluorouracil (5-FU) against two different human brain tumor cell lines (T98G and U118), while primer human dermal fibroblast cells (HDF) was used as control for biocompatibility. Then, the effectiveness of electroporation (EP) on cytotoxic activities of these compounds has been examined. The cytotoxicities of the 5-FU and new Zn(II) complex, alone or in combination with electroporation, were determined by MTT assay. The Zn(II) complex showed good cytotoxicity against T98G and U118 brain tumor cell lines with IC50 = 282.47 and 297.91 µM respectively, while it was safe on HDF healthy cells with IC50 = 826.72 µM. The 5-FU exhibited less cytotoxicity compared to the Zn(II) complex against T98G (IC50 = 382.35 µM) and U118 (IC50 = 396.56 µM) tumor cell lines. The combined application of Zn (II) + EP decreased the IC50 value by 5.96-fold in T98G cells and 4.76-fold in U118 cells. EP showed a similar effect in its combined application with 5-FU, resulting in a decrease of the IC50 value of 4.22-fold in the T98G cells and 3.84-fold in the U118 cells. In a conclusion, the Zn(II) complex exhibited an anticancer potential against both brain tumor cell lines (T98G and U118) and EP greatly increased the cytotoxicity of Zn(II) complex and 5-FU on these chemotherapy-resistant cells.

Transition metal complexes of a multidentate Schiff base ligand containing pyridine: synthesis, characterization, enzyme inhibitions, antioxidant properties, and molecular docking studies.

A series of Fe(II), Ni(II), and Pd(II) complexes were prepared with a novel Schiff base ligand containing pyridine moiety. The prepared compounds were characterized using FT-IR, 1H and 13 C NMR, UV-Vis, powder XRD, thermogravimetric analysis, mass spectra, magnetic susceptibility, and elemental analysis. The coordination geometry of Fe(II) and Ni(II) complexes were octahedral, where Fe(II) and Ni(II) metal ions were coordinated by an oxygen atom of the carbonyl group, a nitrogen atom of the azomethine moiety, and a phenolic oxygen atom. The Pd(II) complex had square planar geometry. All of the synthesized compounds were tested for their biochemical properties, including enzyme inhibition and antioxidant activities. According to the in vitro DPPH and FRAP antioxidant methods, the Schiff base ligand and its Fe(II)/Pd(II) complexes showed close antioxidant activities against the standards (BHA, BHT, ascorbic acid, and α-tocopherol). Enzyme inhibitions of the metal complexes were investigated against glutathione S-transferase (GST), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) enzymes. The best inhibition value (Ki) was observed for the Ni(II) complex against GST (2.63 ± 0.04 µM). Also, the Pd(II) complex showed the best inhibition value (10.17 ± 1.88 µM) against AChE. Molecular docking specified significant interactions at the active pockets of respective target enzymes. The Ni(II) complex exhibited good binding affinity against both BChE (- 9.0 kcal/mol and 9.36 ± 2.03 µM) and GST (- 7.0 kcal/mol and 2.63 ± 0.04 µM) enzymes.

Synthesis, characterization, powder X-ray diffraction analysis, thermal stability, antioxidant properties and enzyme inhibitions of M(II)-Schiff base ligand complexes.

The Schiff base ligand ((E)-6-methyl-2-(2,3,4-trimethoxybenzylideneamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile) and its cobalt(II) and palladium(II) complexes were successfully prepared. The structure of the compounds was elucidated by various techniques (NMR, FT-IR, powder X-ray diffraction, microanalysis, TGA, magnetic susceptibility, mass spectrometry). The Pd(II) complex showed a square planar geometry and the Co(II) complex had an octahedral geometry. ABTS (2,2-azino-bis 3-ethylbenzothiazloine-6-sulphonic acid), DPPH (1,1-diphenyl-2-picrylhydrazyl), FRAP (ferric-reducing antioxidant power) and CUPRAC (cupric reducing antioxidant capacity) in vitro methods were applied to identify the antioxidant features of the synthesized compounds. In addition, glutathione S-transferase and acetyl/butyryl cholinesterase enzymes were examined for possible inhibition capacities of the complexes. According to the enzyme activity measurements, Ru(II) complex inhibited both GST and BChE enzymes, while Fe(II) complex inhibited only AChE enzyme. Furthermore, the antioxidant activities and enzyme inhibitions of the previously synthesized Fe(II) and Ru(II) complexes of the same ligand were examined to make a comparison of the metal complexes.Communicated by Ramaswamy H. Sarma.

Spectroscopic and Structural Characterization, Enzyme Inhibitions, and Antioxidant Effects of New Ru(II) and Ni(II) Complexes of Schiff Base.

The new complex compounds [RuLCl(p-cymene)] ⋅ 3H2 O and [NiL2 (H2 O)2 ] ⋅ 3H2 O (L: 1-{4-[(2-hydroxy-3-methoxybenzylidene)amino]phenyl}ethanone) were prepared and characterized using FT-IR, 1 H- and 13 C-NMR, mass spectroscopy, TGA, elemental analysis, X-ray powder diffraction and magnetic moment techniques. Octahedral geometry for new Ni(II) and Ru(II) complexes was proposed. Thermal decomposition confirmed the existence of lattice and coordinated water molecule in the complexes. To determine the antioxidant properties of Schiff base ligand and its Ni(II), Ru(II) metal complexes, FRAP, CUPRAC, ABTS and DPPH methods of antioxidant assays were used. Moreover, enzyme inhibition of complexes was evaluated against carbonic anhydrase I and II isoenzymes (CA I and CA II) and acetylcholinesterase (AChE). For CA I and CA II, the best inhibition enzymes, was the Ni(II) complex with 62.98±18.41, 86.17±23.62 Ki values, whereas this inhibition effect showed ligand with 24.53±2.66 Ki value for the AChE enzyme.

Synthesis, Structural Characterization and Biological Activity of Novel Cyclohexane-1,3-dione Ligands and Their Metal Complexes.

Some new Zn(II) and Cu(II) complexes [Cu(L1)(OAc)2]∙H2O, [Cu(L1)(NO3)H2O]∙NO3∙3.5H2O, [Zn(L1)(NO3)2]∙4.5H2O, [Zn(L1)(OAc)2(H2O)2]∙3H2O, [Cu2(L2)(OAc)4]∙2H2O∙2DMF, [Cu(L2)2]∙2NO3∙1.5DMF∙H2O, [Zn(L2)2(NO3)2]∙DMF and [Zn2(L2)(OAc)4(H2O)4]∙5H2O; L1 = 2-[2-(2-methoxyphenyl)hydrazono]cyclohexane-1,3-dione and L2 = 2-[2-(3-nitrophenyl)hydrazono]cyclohexane-1,3-dione were synthesized and characterized by IR, 1H-NMR,13C-NMR and ultraviolet (UV-Vis.) spectroscopy, elemental analysis, magnetic susceptibility, mass spectrometry and thermogravimetry-differential thermal analysis (TGA-DTA). The synthesized ligands and their complexes were tested for antibacterial activity against Escherichia coli ATCC 25922, Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 25923, and Salmonella typhimurium CCM 583. Some of complexes showed medium-level antibacterial activity against the test bacteria compared with ampicillin.

Pro-oxidant and antiproliferative effects of the 1,3,4-thiadiazole-based Schiff base and its metal complexes.

Adverse biological activities of Schiff base (SB) derivatives are well known. In this study, the ligand and its metal complexes have been synthesized and characterized by IR, (1)H-NMR spectra, elemental analyses, magnetic susceptibility, UV-Vis spectra, and thermogravimetry/differential thermal analysis. From the elemental analyses data, the complexes were proposed to have the general formula [Mn(L)(2)(H(2)O)(2)], [Co(L)(2)(H(2)O)(2)], and [Ni(2)(L)(H(2)O)(4)(Cl)(3)]. From the magnetic moment and UV-Vis spectra data, it was found that the geometrical structures of these complexes are octahedral. In the in vivo experiment, adult male rats were injected subcutaneously with a new SB (L) and its [Mn(L)(2)(H(2)O)(2)], [Co(L)(2)(H(2)O)(2)], and [Ni(2)(L)(H(2)O)(4)(Cl)(3)] complexes (25 mg/kg body weight) and were then sacrificed 16 days later. Effects of these compounds on serum antioxidant vitamins (i.e., vitamins A, E, and C) and malondialdehyde (MDA) levels were measured in blood serum, liver, and kidney tissues. In an in vitro experiment, antiproliferative effects of these compounds were assessed on the human breast carcinoma MCF-7 and murine leukemia L1210 cell lines. Serum MDA and vitamins A, E, and C levels did not change by the treatments. However, in the kidney and liver tissues, MDA levels were higher, whereas vitamin levels were lower in treatment groups, compared to the control group. All compounds inhibited cell proliferation of MCF-7 and L1210 cancer cell lines in a dose- and time-dependent manner. In conclusion, SB derivatives tested in the current study induced oxidative stress in vivo and exhibited anti-proliferative effects in an in vitro culture system.