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

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Abstract

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 line 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 line. 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.

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... Schiff bases are an important class of ligands due to their structural versatility, straightforward synthesis, and capacity to form stable complexes (32,33). Due to their distinctive photophysical and chemical properties, Schiff bases can be used in a variety of research areas including medicinal and analytical chemistry (34,35). ...
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... Most of the studies for ECT have used 1 or 8 square wave pulse trains with a width of 100 µs and a frequency of 1Hz or 5kHz [4,11,14,15]. While investigating the optimum electroporation conditions, generally keeping these parameters constant, only the electric field was changed [16,17]. In some studies, when the electric field is reduced, the pulse width is increased [18,19]. ...
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Two copper(II) complexes, [Cu2(L¹)2]·2H2O (1) and [Cu3(L¹)2(NCS)2] (2), and two nickel(II) complexes, [NiL²(NCS)] (3) and [Ni(L²)2(NCS)]·CH3OH (4), were prepared from the fluorine substituted Schiff bases N,N'-bis(4-fluorosalicylidene)-1,2-diaminopropane (H2L¹) and 4-fluoro-2-[(2-isopropylaminoethylimino)methyl]phenol (HL²), respectively. The compounds were characterized by physico-chemical methods. Structures of the complexes were further confirmed by single crystal X-ray diffraction. The Cu ions in 1 are square pyramidal, and in 2 are square planar and octahedral. The Ni ion in 3 is square planar, and in 4 is octahedral. All the complexes have effective Jack bean urease inhibitory activities. Complex 1 has the most effective activity, with an IC50 value of 2.1 ± 1.3 μmol L⁻¹.
Article
This review summarizes the use of high-voltage electrical pulses (HVEPs) in clinical oncology to treat solid tumors with irreversible electroporation (IRE) and electrochemotherapy (ECT). HVEPs increase the membrane permeability of cells, a phenomenon known as electroporation. Unlike alternative ablative therapies, electroporation does not affect the structural integrity of surrounding tissue, thereby enabling tumors in the vicinity of vital structures to be treated. IRE uses HVEPs to cause cell death by inducing membrane disruption, and it is primarily used as a radical ablative therapy in the treatment of soft-tissue tumors in the liver, kidney, prostate, and pancreas. ECT uses HVEPs to transiently increase membrane permeability, enhancing cellular cytotoxic drug uptake in tumors. IRE and ECT show immunogenic effects that could be augmented when combined with immunomodulatory drugs, a combination therapy the authors term electroimmunotherapy. Additional electroporation-based technologies that may reach clinical importance, such as gene electrotransfer, electrofusion, and electroimmunotherapy, are concisely reviewed. HVEPs represent a substantial advancement in cancer research, and continued improvement and implementation of these presented technologies will require close collaboration between engineers, interventional radiologists, medical oncologists, and immuno-oncologists.
Article
Basal cell carcinoma (BCC) are the commonest cutaneous malignancy and incidence continues to increase. There is a need to expand the therapeutic toolbox to increase options for patients that are unsuitable for or unwilling to undergo the current therapies. Electrochemotherapy (ECT) is a technique where cells are temporarily permeabilized after exposure to a brief pulsed electrical field and combined with low dose chemotherapeutics to ablate malignancies. It is a simple technique causing minimal damage to the surrounding healthy tissue and has the potential to avoid the need for complex reconstruction. ECT is an established treatment for skin metastases but its role as a primary treatment modality is not demonstrated. A prospective randomised control trial evaluating ECT against the gold standard of treatment, Surgery, was performed for patients with primary BCC and patients followed for 5 years. All lesions treated with ECT (n = 69) responded although 8/69 (12%) needed a second treatment to ensure a complete response. All surgical lesions (n = 48) showed histological evidence of complete excision with 2/48 (4%) undergoing a second excision. At 5 years, in the surgical arm there was no evidence of recurrence in 39/40 (97.5%) lesions with 1/40 (2.5%) confirmed recurrence. In the ECT arm there was no evidence of recurrence in 42/48 lesions (87.5%). There was 5 confirmed recurrences. These groups show statistical equivalence in this non inferiority study design (p = 0.33). ECT is an effective and durable treatment option for primary BCC and should be considered as part of the armamentarium of options available.
Article
Two Schiff base ligands namely bis-2-((1E)-((Z)-2-(1,2-diphenylethylideneamino) phenylimino)methyl)phenol (L1) and bis-2-((1E)-((E)-2-(1-phenylethylideneamino)phenylimino) methyl)phenol (L2) were synthesized by tailored reaction of o-phenylenediamine with o-hydroxybenzaldehyde and 2-hydroxy-1,2-diphenylethanone/o-hydroxyacetophenone. The reaction of these ligands with Fe(III), Co(II), and Ni(II) salts yielded six complexes. Ligands and their metal derivatives have been characterized by elemental analysis, molar conductance, magnetic susceptibility, FT-IR, UV–Vis, ESI-mass, ¹H NMR, ¹³C NMR and EPR analysis. Using Gaussian 09 molecular modelling, bond lengths, bond angles and Mulliken charge were also evaluated. In addition to this study of HOMO and LUMO molecular orbital have been performed. The FT-IR spectra have suggested that ligand is coordinated with metal through azomethine-N and phenolic-O. Experimental and theoretical IR and NMR spectrum of ligand L1 and complex 2 exhibits quite good correlation. ESR spectrum of complex 2 at LNT suggests octahedral geometry around Co(II). Complexes were studied for their oxygen-binding activity and displayed significant oxygenation reaction. The thermodynamic parameters such were also calculated. The compounds were screened for antibacterial activity against gram-negative bacteria Escherichia coli and compared with Amoxicillin. Complexes have exhibited significant antibacterial activity. The corrosion inhibition effect of ligands and complexes on mild steel in acidic medium was studied for 24, 48 and 72 h using weight loss measurement.
Article
Herein we describe the chemical synthesis of a novel tetradentate Schiff base ligand (H2L), bridged with a pyridine, and its corresponding mononuclear copper complex (Cu(II)L). H2L, derived from the condensation of 2,3-diaminopyridine and 5-bromosalicylaldehyde, and Cu(II)L were structurally confirmed by routine spectral techniques, UV–Vis, FT-IR, 1H NMR, MS and elemental analysis. Single crystal X-ray diffraction analysis of Cu(II)L complex showed a monoclinic system with P21/C space group and Z = 4 molecules per unit cell. The characterization data of the complex revealed strong coordination via azomethine nitrogen (N) and bromo-phenolate oxygen (O). Moreover, the experimental parameters were found in line with the theoretical parameters. The conductivity measurement showed a non-electrolytic nature of the complex and the electrochemical behavior exhibits two quasi reversible redox processes. In-vitro antimicrobial studies on the synthesized compounds revealed a significant activity of the complex on some bacteria strains than the free ligand. DFT calculations were fully optimized using B3LYP and confirmed practical electrochemical and antibacterial results.
Article
A new dimeric Ni(II) complex, [Ni2L12(CH3CN)4](ClO4)2·2CH3CN (1) has been synthesized by an N2O donor reduced Schiff base [(HL1)= 2-[(3-methylamino-propylamino)-methyl]-4-phenol]. Surprisingly, in an attempt to replace its ClO4- ion by SCN-, the N2O donor ligand in situ converts to a tetradentate N2O2 donor ligand and forms metal complex, [Ni(HL2)(NCS)(CH3CN)] (2). A probable mechanism via deaminative coupling for this conversion is proposed. Using 2 as metalloligand under basic condition, a trinuclear metal complex, [Ni3(L2)2(NCS)2(H2O)4]·H2O (3) has been prepared. Single crystal structural characterization reveals that in all three metal complexes, the Ni(II) atoms are in octahedral environment with coordinated solvent molecules (CH3CN in 1 and 2 and H2O in 3). Among the three metal complexes, 1 and 3 show catecholase like biomimicking activity. The calculation of turnover numbers (Kcat = 7.9 for 1, 14.5 for 3) reveals that 3 is better catalyst than 1. Mechanistic cycles are proposed for this biomimicking activity on the basis of ESI-MS spectrometry and iodometric measurements. Temperature dependent magnetic susceptibility measurements suggest that Ni(II) ions in metal complexes 1 and 3 are antiferromagnetically coupled (J = –32.22 cm-1 for 1, J = –10.4 cm-1 for 3), consistent with their geometries and bridging angles. Theoretically calculated J values (J = –40.15 cm-1 for 1, J = –14.53 cm-1 for 3) by DFT method corroborate well the experimental values.
Article
Electrochemotherapy (ECT) exploits the phenomenon of electroporation, which is the increase of cell permeability through the application of an electrical field. This technique is applied in medical centers in Europe and in veterinary clinics in Europe, Brazil, and Argentina. ECT treatment requires a minimum electric field and anti-cancer drugs (e.g., bleomycin). Irregularly shaped tumors may induce ECT treatment failure because of irregular electric field distribution. Conductive gels have been suggested as a means to increase the homogeneity of the electrical field distribution. The aim of this work was to evaluate if commercial conductive gels could increase the safety of ECT. A veterinary case study of ECT in a dog provided the tumor dimensions for the numerical model. Electrode displacement and commercial conductive gels were simulated to determine if they improved ECT treatments. We conclude that a commercial gel having a conductivity of 0.2 S/m when used in combination with effective treatment planning may improve the outcome of electrochemotherapy procedures.
Article
Curcumin (Cur), the yellow pigment of well-known turmeric (Curcuma longa L.) is effective in multiple cancers including triple negative breast cancer (TNBC). In combination with electrical pulses (EP), enhanced effects of curcumin (Cur + EP) are observed in TNBC cells. To gain insights into the mechanisms of enhanced anticancer effects of Cur + EP, we studied the proteins involved in the anticancer activity of Cur + EP in MDA-MB-231, human TNBC cells using high-throughput global proteomics. A curcumin dose of 50 μM was applied with eight, 1200 V/cm, 100 μs pulses, the most commonly used electrochemotherapy (ECT) parameter in clinics. Results show that the Cur + EP treatment reduced the clonogenic ability in MDA-MB-231 cells, with the induction of apoptosis. Proteomic analysis identified a total of 1456 proteins, of which 453 proteins were differentially regulated, including kinases, heat shock proteins, transcription factors, structural proteins, and metabolic enzymes. Eight key glycolysis proteins (ALDOA, ENO2, LDHA, LDHB, PFKP, PGM1, PGAM1 and PGK1) were downregulated in Cur + EP from Cur. There was a switch in the metabolism with upregulation of 10 oxidative phosphorylation pathway proteins and 8 tricarboxylic acid (TCA) cycle proteins in the Cur + EP sample, compared to curcumin. These results provide novel systematic insights into the mechanisms of ECT with curcumin.
Article
A series of new Zn II , Co II/III and Ni II complexes derived from reduced Schiff base 6,6′-((propane-1,3-diylbis(azanediyl))bis(methylene))bis(2-ethoxyphenol) (H 2 L), [Zn 3 L 2 (N 3 ) 2 ] (1), [Co 2 L(N 3 ) 2 (CH 3 COO)]·CH 3 OH (2) and [Ni(HL)(OH 2 )(CH 3 OH)]·ClO 4 (3), were prepared and characterized by physico-chemical methods. Crystal structures of the complexes were determined by single crystal X-ray diffraction. Complex 1 is a trinuclear zinc(II) compound. Complex 2 is a dinuclear cobalt(II/III) compound. Complex 3 is a mononuclear nickel(II) compound. The cobalt complex and the nickel complex have effective urease inhibitory activities, with IC 50 values of 19.8 and 11.6 μmol·L ⁻¹ , respectively. However, the zinc complex 1 has no such activity. Molecular docking study of complexes 2 and 3 with the active center of Jack bean urease was studied.
Article
To develop potential next-generation metal anticancer agents, we designed and synthesised five Cu(II) 2-pyridine-thiosemicarbazone complexes by modifying the hydrogen atom at the N-4 position of ligands, and then investigated their structure-activity relationships and anticancer mechanisms. Modification of the N-4 position with different groups caused significant differences in cellular uptake and produced superior antitumor activity. Cu complexes arrested the cell cycle at S phase, leading to down-regulation of levels of cyclin and cyclin-dependent kinases and up-regulation of expression of cyclin-dependent kinase inhibitors. Cu complexes exerted chemotherapeutic effects via activating p53 and inducing production of reactive oxygen species to regulate expression of the B-cell lymphoma-2 family of proteins, causing a change in the mitochondrial membrane potential and release of cytochrome c to form a dimer with apoptosis protease activating factor-1, resulting in activation of caspase-9/3 to induce apoptosis. In addition, Cu complexes inhibited telomerase by down-regulating the c-myc regulator gene and expression of the human telomerase reverse transcriptase.
Article
In the search for more effective anticancer drugs with less toxic side effects, dipeptides were introduced into the Cu(II) complex of 5-methyl-2-(2'-pyridyl)benzimidazole (HPBM). Analytical and spectroscopic techniques were employed to thoroughly characterize complexes [Cu(Gly-gly)(HPBM)(H2O)]ClO4·0.5H2O (1) and [Cu(Gly-L-leu)(HPBM)(H2O)]ClO4 (2) (where Gly-gly = Glycyl-glycine anion, Gly-L-leu = Glycyl-l-leucine anion). The solution stability studies performed by ultraviolet-visible (UV-Vis) spectroscopy confirmed the stability of the complexes in the buffer solutions. The DNA binding affinity was evaluated using multi-spectroscopy, viscosity measurement and molecular docking methods and further quantified by Kb and Kapp values, revealing an intercalative mode. Moreover, gel electrophoresis analysis revealed that the complexes could damage CT DNA through a hydroxyl radical pathway in the presence of ascorbic acid. All the complexes displayed favorable antimicrobial and cytotoxic activities toward the tested microorganisms (Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa) and cancer cells (A549, HeLa and PC-3). Most importantly, the possible anticancer mechanism of the complexes was explored by determining the cells morphological changes, intracellular reactive oxygen species (ROS) levels, location in mitochondria, mitochondrial membrane potentials and the expression of Bcl-2 family proteins. The results showed that the complexes could induce apoptosis in HeLa cells through an ROS-mediated mitochondrial dysfunction pathway, which was accompanied by the regulation of Bcl-2 family proteins.
Article
In this study, a series of unsymmetrically 2-morpholinoethyl-substituted benzimidazolium salts and their Ag(I)NHC complexes were synthesized. The 1,3-dialkylbenzimidazolium salts (1a–d) were synthesized in dimethylformamide at 80 °C temperature from the N-(2-morpholinoethyl)benzimidazole and alkyl halides. The Ag(I)NHC complexes (2a–d) were synthesized in dichloromethane at room temperature from the benzimidazolium salts and Ag2O. All compounds were characterized by spectroscopic techniques (NMR and FT-IR) and elemental analyses. Also, the salt 1c and complex 2c were characterized by single-crystal X-ray crystallography. Anticancer activities of 2-morpholinoethyl-substituted benzimidazolium salts and Ag(I)NHC complexes were investigated against the MCF-7 breast cancer cell line, and the IC30 and IC50 values of these compounds were found to be in the range of 241–490 and 6–14 µM, respectively.
Article
Four benzimidazole-based Cu(II) complexes: Cu2(p-2-bmp)2Br4 (1), Cu2(p-2-bmp)2Cl4 (2), Cu2(p-2-bmb)2(DMF)2Br4·(CHCl3) (3), and Cu(p-2-bmb)(NO3)2·(CHCl3) (4) were isolated and characterized, where p-2-bmp is 1-((2-(pyridine-2-yl)-1H-benzoimidazol-1-yl)methyl)-1H-pyridine and p-2-bmb is 1-((2-(pyridin-2-yl)-1-benzoimidazol-1-yl)methyl)-1H-benzotriazole. Complexes 1 and 2 have binuclear configurations, 3 has a mononuclear structure, and 4has a one-dimensional (1-D) chain skeleton. To evaluate their potential anticancer effects on human carcinoma cells, anti-proliferation, DNA binding and cleavage, and apoptosis elicitation were examined. Compared with complexes 2, 3, and 4, complex 1 exhibited potent in vitro cytotoxicity toward four cell lines (MCF7, EC109, SH-SY5Y and QBC939), with SH-SY5Y cells demonstrating the most sensitivity. Therefore, further in-depth investigations were performed using complex 1. Absorption titration experiments, circular dichroism spectroscopic studies, and ethidium bromide displacement assays suggested that complex 1 binds to DNA through intercalation, significantly cleaves supercoiled pBR322 DNA, and inhibits DNA transcription. Cell cycle analysis revealed that SH-SY5Y cells were arrested in the G2/M phase after treatment with complex 1. Membrane permeability analysis and nuclear staining of SH-SY5Y cells showed that complex 1 could induce apoptosis.
Article
A new series of transition metal complexes of mercapto pyrimidine Schiff base complexes has been studied and characterized using various spectral techniques like single crystal XRD, FT-IR, electronic, EDX and TGA. The molecular properties of the ligand and the complexes have been derived from HOMO-LUMO calculations using Gaussian software. The biological evaluation of the ligands and the complexes has been studied and compared. The DNA binding studies of the complexes has been carried out and the binding constants are in the order of 10⁴ M⁻¹. The DNA cleavage activity of the complexes proves the mechanism of cleavage is through non-hydrolytic pathway.
Article
Novel ether based Schiff bases (HL1- HL4) were synthesized from 5-chloro-2-hydroxy benzaldehyde and primary amines (1-amino-4-phenoxybenzene, 4-(4-aminophenyloxy) biphenyl, 1-(4-aminophenoxy) naphthalene and 2-(4-aminophenoxy) naphthalene). From these Schiff bases copper(II) complexes (Cu(L1)2-Cu(L4)2)) were synthesized and characterized by elemental analysis and spectroscopic (FTIR, NMR) techniques. The synthesized Schiff bases and copper(II) complexes were further assessed for various biological studies. In brine shrimp assay the copper(II) complexes revealed 4-fold higher activity (LD50 3.8 μg/ml) as compared with simple ligands (LD50 12.4 μg/ml). Similar findings were observed in potato disc antitumor assay with higher activities for copper(II) complexes (IC50 range 20.4–24.1 μg/ml) than ligands (IC50 range 40.5–48.3 μg/ml). DPPH assay was performed to determine the antioxidant potential of the compounds. Significant antioxidant activity was shown by the copper(II) complexes whereas simple ligands have shown no activity. In DNA protection assay significant protection behavior was exhibited by simple ligand molecules while copper(II) complexes showed neutral behavior (neither protective nor damaging).
Article
The complexes of Fe(II), Cd(II) and Zn(II) with Schiff base derived from 2-amino-3-hydroxypyridine and 3-methoxysalicylaldehyde have been prepared. Melting points, decomposition temperatures, Elemental analyses, TGA, conductance measurements, infrared (IR) and UV – Visible spectrophotometric studies were utilized in characterizing the compounds. The UV-Visible spectrophotometric analysis revealed 1:1 (metal-ligand) stoichiometry for the three complexes. In addition to, the prepared complexes have been used as precursors for preparing their corresponding metal oxides nanoparticles via thermal decomposition. The structures of the nano-sized complexes and their metal oxides were characterized by X-ray powder diffraction and transmittance electron microscopy. Moreover, the prepared Schiff base ligand, its complexes and their corresponding nano-sized metal oxides have been screened in vitro for their antibacterial activity against three bacteria, gram-positive (Microccus luteus) and gram-negative (Escherichia coli, Serratia marcescence) and three strains of fungus. The metal chelates were shown to possess more antimicrobial activity than the free Schiff-base chelate and their nano-sized metal oxides have the highest activity. The binding behaviors of the complexes to calf thymus DNA have been investigated by absorption spectra, viscosity mensuration and gel electrophoresis. The DNA binding constants reveal that all these complexes interact with DNA through intercalative binding mode. Furthermore, the cytotoxic activity of the prepared Schiff base complexes on human colon carcinoma cells, (HCT-116 cell line) and hepatic cellular carcinoma cells, (HepG-2) showed potent cytotoxicity effect against growth of carcinoma cells compared to the clinically used Vinblastine standard.
Article
New dimer complexes of zinc(II), copper(II) and nickel(II) were synthesized using the Schiff base ligand which was formed by the condensation of 2-aminothiophenol and 2-hydroxy-5-methyl benzaldehyde. This tridentate Schiff base ligand was coordinated to the metal ions through the NSO donor atoms. In order to prevent the oxidation of the thiole group during the formation of Schiff base and its complexes, all of the reactions were carried out under an inert atmosphere of argon. The X-ray structure of the Schiff base ligand showed that in the crystalline form the SH groups were oxidized to produce a disulfide Schiff base as a new double Schiff base ligand. The molar conductivity values of the complexes in dichloromethane implied the presence of non-electrolyte species. The fluorescence properties of the Schiff base ligand and its complexes were also studied in dichloromethane. The products were characterized by FT-IR, 1H NMR, UV/Vis spectroscopies, elemental analysis, and conductometry. The crystal structure of the double Schiff base was determined by single crystal X-ray diffraction. Furthermore, the density functional theory (DFT) calculations were performed at the B3LYP/6-31G(d,p) level of theory for the determination of the optimized structures of Schiff base complexes.
Conference Paper
Background: Iron overload is a leading cause of morbidity and mortality in beta thalassemia and chelation therapy remains the mainstay in reducing iron burden. For effective chelation, optimal drug dosage with close monitoring of side effects is crucial. The safety and efficacy of deferasirox has been extensively studied in adult population. We aimed at evaluating the liver enzyme changes and safety profile of deferasirox in pediatric patients with thalassemia major. Materials and Methods: A retrospective study of 30 patients (range 2-15 years) with thalassemia major on regular follow up at the Pediatric Day care Center, Sultan Qaboos University Hospital was performed to evaluate the side effects of deferasirox over a mean of 15 month follow-up period. Data from electronic patients' records was collected for age, gender, serum ferritin, alanine transaminase, (ALT), aspartate transaminase (AST), dose and side effects of deferasirox. Data were analyzed using SPSS software version 19. Results: Thirteen (44.8 %) patients had either ALT or AST elevation above 2 times upper limit of normal (ULN). Except for two (6.8%) patients with enzyme elevations more than 5 times ULN, the majority of patients had mild transaminitis. None of the patients had liver enzyme elevation above 10 times ULN. The other side effects included fever (17.24%), nausea and vomiting (10.34% each), diarrhoea (13.79%), skin rash (21.4%), elevated serum creatinine with either 2 consecutive readings more than 33% of baseline level and/or single reading above 60% baseline (17.24%). The mean serum ferritin dropped from initial baseline level of 1236.21 ± 354 ng/ml (Range 534 -2821 ng/ml) to a level of 950 ± 320 ng/ml (Range 550-1900 ng/ml) at the end of the study period; with a mean deferasirox dose of 32.72 ± 4.79 mg/kg/day. Conclusion: Majority of our patients had mild transaminitis not requiring dose modification or interruption of chelation. Patients with significant elevations of liver enzymes more than 5 times ULN showed prompt recovery of transaminitis within 4-5 weeks of dose reduction of deferasirox by 5 mg/kg/day and future dose increments were well tolerated. Except for significant elevations in serum creatinine requiring dose reduction or short interruption, the other adverse events were well tolerated and did not warrant dose modification. Deferasirox was effective in reducing serum ferritin levels and was well tolerated in our young patients with thalassemia major. Table 1 PatientCharacteristics Numberof patients, n 30 Meanage of patients, years Range,years 7.24± 3.4 2-15 Meanserum ferritin, ng/ml Range,ng/ml 1236.21± 354 534-2821 Meandose of deferasirox (mg/kg/day) 32.72± 4.79 Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.
Article
The electroporation (EP) supports various types of anticancer therapies by the selective transport of cytostatics. Increase in intracellular calcium level by EP may be a new approach to fibrosarcoma treatment. Calcium is one of the most important factor of cell proliferation, differentiation and cell death (apoptosis or necrosis). Calcium level balanced by electroporation can cause different effect on normal and pathological cells. The efficiency and safety of electroporation combined with Ca2 + ions was examined in our study. The two muscle cell lines were used: normal rat skeletal muscle cells – L6 and cancer muscle cells – Wehi-164 (fibrosarcoma). Two CaCl2 concentrations were tested: 0.5 mM and 5 mM combined with EP parameters: 1000 V/cm, 1200 V/cm, 1500 V/cm. The results show that EP supported by Ca2 + is cytotoxic for Wehi-164 cells and simultaneously safe for normal muscle cells. The main type of cell death – apoptosis was confirmed by Tunnel and Annexin V/PI assay. Additionally, sPLA2 pro-tumorigenic influence was proved by immunocytochemistry. Moreover, EP with 0.5 mM of Ca2 + slightly stimulates the normal muscle cells – L6 to increase proliferation.
Article
A novel Schiff base ligand (H2L) was prepared through condensation of 2,6-diaminopyridine and o-benzoylbenzoic acid in a 1:2 ratio. This Schiff base ligand was characterized using elemental and spectroscopic analyses. A new series of Cr(III), Mn(II), Fe(III), Co(II), Ni(II), Cu(II), Zn(II) and Cd(II) metal complexes of H2L were prepared and characterized using elemental analysis, spectroscopy (1H NMR, mass, UV-visible, Fourier transform infrared, electron spin resonance), magnetic susceptibility, molar conductivity, X-ray powder diffraction and thermal analysis. The complexes are found to have trigonal bipyramidal geometry except Cr(III), Mn(II) and Fe(III) complexes which have octahedral geometry based on magnetic moment and solid reflectance measurements. The infrared spectral studies reveal that H2L behaves as a neutral bidentate ligand and coordinates to the metal ions via the two azomethine nitrogens. 1H NMR spectra confirm the non-involvement of the carboxylic COOH proton in complex formation. The presence of water molecules in all reported complexes is supported by thermogravimetric studies. Kinetic and thermodynamic parameters were determined using Coats-Redfern and Horowitz-Metzger equations. The synthesized ligand and its complexes were screened for antimicrobial activities against two Gram-positive bacteria (Bacillus subtilis and Staphylococcus aureus), two Gram-negative bacteria (Escherichia coli and Neisseria gonorrhoeae) and one fungus (Candida albicans). Anticancer activities of the ligand and its metal complexes against human breast cancer cell line (MCF7) were investigated.
Article
The revelation of the anticancer properties of cisplatin has inspired research into metal complexes for the treatment of cancer. Several second and third generation cisplatin analogues were developed with claims of good anticancer properties and reduced side effects. However, the persistence of some side effects and the resistance of cancer cells have tempted scientists to explore new metal complexes as anticancer drugs. Therefore, the approach of rational drug design has been extended to the development of non-platinum anticancer drugs, and a large number of such complexes have been developed. Iron complexes are of interest to inorganic medicinal chemists for the development of anticancer agents. The anticancer potency of iron complexes was first reported in ferrocenium picrate and ferrocenium trichloroacetate salts, and was attributed to their ability to form reactive oxygen species, leading to oxidative DNA damage. This review discusses the advances in iron complexes as anticancer agents. The aspects of the photocytotoxicity, redox activity and multinuclearity of anticancer iron complexes are discussed, in addition to discussing ferrocenyl derivatives and salen complexes. The legacy of nanotechnology and synergism in harnessing the potential of iron complexes is highlighted. Finally, the current challenges and future perspectives of iron complexes as anticancer agents are outlined.
Article
The research on copper(I,II) coordination compounds as antiproliferative agents has increased as demonstrated by the high number of papers published in this field in the period 2008-2012. The first consideration which stems from the presented data concerns the large variety of ligands used to synthesize potentially active copper drugs. The reported copper complexes (mostly copper(II)) comprised ligands of different hapticity, from monodentate to hexadentate, and characterized by different donor atoms (O, N, S, P, and C) which gave rise to different geometrical arrangements and, in some cases, dimeric and polymeric species. Regarding the copper oxidation state, there is no direct correlation between the antiproliferative activity and reduced or oxidized forms of the metal. However, the few reported copper(I) complexes, featured by phosphine or heterocyclic carbene ligands generally showed a potent cytotoxic activity. Most of the studies with copper complexes continue to consider DNA as the main biological target.
Article
Novel Co(II), Ni(II), Cu(II) and Zn(II) complexes of Schiff base derived from quinoxaline-2,3-(1,4H)-dione and 4-aminoantipyrine (QDAAP) were synthesized. The ligand and its complexes were characterized by elemental analyses, molar conductance, magnetic susceptibility measurements, FTIR, UV-Vis., mass and (1)H NMR spectral studies. The X band ESR spectrum of the Cu(II) complex at 300 and 77K were also recorded. Thermal studies of the ligand and its complexes show the presence of coordinated water in the Ni(II) and Zn(II) complexes. The coordination behavior of QDAAP is also discussed. All the complexes are mono nuclear and tetrahedral geometry was found for Co(II) complex. For the Ni(II) and Zn(II) complexes, octahedral geometry was assigned and for the Cu(II) complex, square planar geometry has been suggested. The grain size of the complexes was estimated using powder XRD. The surface morphology of the compounds was studied using SEM analysis. Electrochemical behavior of the synthesized complexes in DMF at room temperature was investigated by cyclic voltammetry. The in vitro biological screening of QDAAP and its metal complexes were tested against bacterial species Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. The fungal species include Aspergillus niger, Aspergillus flavus and Candida albicans. The DNA cleavage activity of QDAAP and its complexes were also discussed.