RESUMEN
Metal complexes showing dual activity against cancer and bacterial infections are currently the focus of significant interest for their potential in treating life-threatening diseases. Aiming to investigate the impact of ligand substituents on these bioactivity properties of Group 11 d10 metal complexes, we herein present a series of mononuclear Cu(I) and Ag(I) complexes featuring the bis-NH2-substituted heterocyclic thioamide dap2SH (=4,6-diaminopyrimidine-2-thione), namely [AgCl(dap2SH)(PPh3)2] (1), [CuBr(dap2SH)(PPh3)2] (2), [CuBr(dap2SH)(xantphos)] (3), [Ag(dap2S)(xantphos)] (4), and [Cu(dap2S)(xantphos)] (5) (xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene). Complexes were characterized by means of different physicochemical methods (i.e., single crystal X-ray diffraction as well as FTIR, NMR, UV-Vis and fluorescence spectroscopy), and studied in-vitro for their antibacterial and anticancer activity against a variety of bacterial strains and cancer cell lines. Complexes 1-3 effectively inhibited both Gram (+) and Gram (-) bacterial growth, while cellular uptake studies for the most potent complex 1 against E. coli bacteria revealed the accumulation of Ag(I) ions in the periplasm of the bacteria. A high anti-proliferative effect was observed for 1 and 5 against A549, MCF7 and PC3 cancer cell lines, with 1 being capable of inducing apoptosis in A549 cells, as suggested by flow cytometry analysis. DNA interaction studies revealed the capacity of 1 to intercalate between base-pairs of CT DNA. All complexes had a moderate-to-high capacity to scavenge free radicals preventing oxidative stress. Molecular docking calculations, in combination with the experimentally obtained data, provided insights for potential mechanisms of the bioactivity of the complexes.
Asunto(s)
Antibacterianos , Antineoplásicos , Complejos de Coordinación , Cobre , Ensayos de Selección de Medicamentos Antitumorales , Escherichia coli , Pruebas de Sensibilidad Microbiana , Plata , Tioamidas , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Escherichia coli/efectos de los fármacos , Humanos , Cobre/química , Cobre/farmacología , Tioamidas/química , Tioamidas/farmacología , Tioamidas/síntesis química , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Plata/química , Plata/farmacología , Estructura Molecular , Relación Estructura-Actividad , Aminas/química , Aminas/farmacología , Aminas/síntesis química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Línea Celular Tumoral , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/síntesis químicaRESUMEN
Melanoma, arguably the deadliest form of skin cancer, is responsible for the majority of skin-cancer-related fatalities. Innovative strategies concentrate on new therapies that avoid the undesirable effects of pharmacological or medical treatment. This article discusses the chemical structures of [(MTZ)2AgNO3], [(MTZ)2Ag]2SO4, [Ag(MCZ)2NO3], [Ag(MCZ)2BF4], [Ag(MCZ)2SbF6] and [Ag(MCZ)2ClO4] (MTZ-metronidazole; MCZ-miconazole) silver(I) compounds and the possible relationship between the molecules and their cytostatic activity against melanoma cells. Molecular Hirshfeld surface analysis and computational methods were used to examine the possible association between the structure and anticancer activity of the silver(I) complexes and compare the cytotoxicity of the silver(I) complexes of metronidazole and miconazole with that of silver(I) nitrate, cisplatin, metronidazole and miconazole complexes against A375 and BJ cells. Additionally, these preliminary biological studies found the greatest IC50 values against the A375 line were demonstrated by [Ag(MCZ)2NO3] and [(MTZ)2AgNO3]. The compound [(MTZ)2AgNO3] was three-fold more toxic to the A375 cells than the reference (cisplatin) and 15 times more cytotoxic against the A375 cells than the normal BJ cells. Complexes of metronidazole with Ag(I) are considered biocompatible at a concentration below 50 µmol/L.
Asunto(s)
Antineoplásicos , Complejos de Coordinación , Melanoma , Metronidazol , Miconazol , Plata , Humanos , Melanoma/tratamiento farmacológico , Melanoma/metabolismo , Melanoma/patología , Miconazol/farmacología , Miconazol/química , Plata/química , Antineoplásicos/farmacología , Antineoplásicos/química , Metronidazol/química , Metronidazol/farmacología , Línea Celular Tumoral , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Supervivencia Celular/efectos de los fármacos , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patologíaRESUMEN
Recognizing that metal ions play an important role in modifying the pharmacological properties of known organic-based drugs, the present manuscript addresses the complexation of the antifungal agent voriconazole (vcz) with the biologically relevant silver(I) ion as a strategy for the development of new antimycotics. The synthesized silver(I) complexes with vcz were characterized by mass spectrometry, IR, UV-Vis and NMR spectroscopy and single-crystal X-ray diffraction analysis. The crystallographic results showed that complexes {[Ag(vcz)(H2O)]CH3SO3}n (1), {[Ag(vcz)2]BF4}n (2) and {[Ag(vcz)2]PF6}n (3) have polymeric structures in the solid state, in which silver(I) ions have a distorted tetrahedral geometry. On the other hand, DFT calculations revealed that the investigated silver(I) complexes 1-3 in DMSO exist as linear [Ag(vcz-N2)(vcz-N19)]+ (1a), [Ag(vcz-N2)(vcz-N4)]+ (2a) and [Ag(vcz-N4)2]+ (3a) species, respectively. The evaluated complexes showed an enhanced anti-Candida activity compared to the parent drug with minimal inhibitory concentration (MIC) values in the range of 0.02-1.05 µM. In comparison with vcz, the corresponding silver(I) complexes showed better activity in prevention hyphae and biofilm formation of C. albicans, indicating that they could be considered as promising agents against Candida that significantly inhibit its virulence. Also, these complexes are much better inhibitors of ergosterol synthesis in the cell membrane of C. albicans at the concentration of 0.5 × MIC. This is also confirmed by a molecular docking, which revealed that complexes 1a - 3a showed better inhibitory activity than vcz against the sterol 14α-demethylase enzyme cytochrome P450 (CYP51B), which plays a crucial role in the formation of ergosterol.
Asunto(s)
Antifúngicos , Complejos de Coordinación , Pruebas de Sensibilidad Microbiana , Plata , Voriconazol , Antifúngicos/farmacología , Antifúngicos/química , Antifúngicos/síntesis química , Voriconazol/farmacología , Voriconazol/química , Plata/química , Plata/farmacología , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Candida albicans/efectos de los fármacos , Candida/efectos de los fármacos , Cristalografía por Rayos XRESUMEN
Two copper(I) polymorphs of formula [Cu(SALH)(TPP)3] (1a and 1b) were prepared by the conjugation of the Non-Steroidal Anti-Inflammatory Drug (NSAID) salicylic acid (SALH2) with the mitochondriotropic agent triphenylphosphine (TPP) via metal ion. For comparison, the isomorph [Ag(SALH)(TPP)3] (2) was prepared. The conjugates 1a, 1b and 2 were characterized by melting point (m.p.), Attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy, Ultraviolet-Visible (UV-Vis) spectroscopy and nuclear magnetic resonance (1H NMR). The crystal structures of 1a, 1b and 2 were confirmed by X-ray diffraction crystallography (XRD). The ex vivo binding affinity of 1-2 towards CT (calf thymus)-DNA was studied by UV, fluorescence, viscosity and DNA Thermal Denaturation studies. Their inhibitory activity against lipoxygenase (LOX) (an enzyme which is mainly located in the mitochondrion) was determined. The in vitro activity of 1-2 was evaluated against human breast cancer cell lines MCF-7 (hormone depended (HD)) and MDA-MB 281 (hormone independent (HI)) cells. Compounds 1-2 inhibit stronger than cisplatin the cancerous cells. The molecular mechanism of action of 1-2 was suspected by the MCF-7 cells morphology and confirmed by DNA fragmentation, Acridine Orange/Ethidium Bromide (AO/EB) Staining and mitochondrial membrane permeabilization tests.
Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Complejos de Coordinación , Humanos , Femenino , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/química , Neoplasias de la Mama/tratamiento farmacológico , Plata/química , ADN/química , Hormonas , Antineoplásicos/farmacología , Antineoplásicos/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , CobreRESUMEN
The healing properties of silver have been used since ancient times. The main aim of the study was to collect and review the literature on the clinical potential of silver, its salts and complex compounds. The second goal was to present an outline of the historical use of silver in medicine and pharmacy, taking into account the possibility of producing pharmaceutical drug forms on the premises of pharmacies. In the context of the growing resistance of microorganisms to available, widely used antibiotics, silver plays a key role. There is only one known case of bacterial resistance to silver-the Pseudomonas stutzeri strain, which naturally occurs in silver mines. The development of research in the field of coordination chemistry offers great opportunities in the design of new substances in which silver ions can be incorporated. These substances exhibit increased potency and often an extended antimicrobial spectrum. Silver-based compounds are, however, only limited to external applications, as opposed to their historic oral administration. Advanced studies of their physicochemical, microbiological, cytotoxic and genotoxic properties are ongoing and full of challenges. The improvement of the methods of synthesis gives the possibility of applying the newly synthesized compounds ex tempore, as was the case with the complex of metronidazole with silver (I) nitrate. Some of these experimental efforts performed in vitro are followed with clinical trials. The third and final goal of this study was to present the possibility of obtaining an ointment under the conditions of an actual pharmacy using silver (I) salts and a ligand, both of which are active substances with antimicrobial properties.
Asunto(s)
Antiinfecciosos , Farmacias , Farmacia , Plata/química , Sales (Química) , Antiinfecciosos/farmacología , Antiinfecciosos/química , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Compuestos de Plata , Preparaciones FarmacéuticasRESUMEN
Three Ag(I) bis(phenanthroline-oxazine) complexes with varying lipophilicity were synthesised and characterised. The solution stoichiometry of 1:2 Ag(I):ligand was determined for each complex by the continuous variation Job's plot method using NMR spectroscopy. NMR studies were also carried out to investigate the fluxional behaviour of the Ag(I) complexes in solution. The biological activity of the silver(I) complexes and the corresponding ligands towards a clinical strain of Candida albicans MEN was studied using broth microdilution assays. Testing showed the choice of media and the duration of incubation were key determinants of the inhibitory behaviour towards Candida albicans, however, the difference between freshly prepared and pre-prepared solutions was insignificant in minimal media. The activity of the metal-free ligands correlated with the length of the alkyl chain. In minimal media, the methyl ester phenanthroline-oxazine ligand was effective only at 60 µM, limiting growth to 67% of the control, while a 60 µM dose of the propyl ester analogue limited fungal growth at < 20% of the control. MIC50 and MIC80 values for the propyl and hexyl ester analogues were calculated to be 45 and 59 µM (propyl), and 18 and 45 µM (hexyl). Moreover, in a study of activity as a function of time it was observed that the hexyl ester ligand maintained its activity for longer than the methyl and propyl analogues; after 48 h a 60 µM dose held fungal growth at 24% of that of the control. Complexation to Ag(I) was much more effective in enhancing biological activity of the ligands than was increasing the ester chain length. Significantly no difference in activity between the three silver(I) complexes was observed under the experimental conditions. All three complexes were substantially more active than their parent ligands against Candida albicans and AgClO4 and the three silver(I) bis(phen-oxazine) complexes have MIC80 values of < 15 µM. The ability of the silver(I) complexes to hold fungal growth at about 20% of the control even after 48 h incubation at low dosages (15 µM) showcases their superiority over the simple silver(I) perchlorate salt, which ceased to be effective at dosages below 60 µM at the extended time point.
Asunto(s)
Candida albicans , Fenantrolinas , Humanos , Fenantrolinas/farmacología , Fenantrolinas/química , Plata/farmacología , Plata/química , Ligandos , Oxazinas/farmacología , Ésteres/farmacologíaRESUMEN
Redox-active azothioformamides (ATFs) contain an NNCS 1,3-heterodiene motif typically found in other molecular subclasses that exhibit a wide range of cytotoxic and anti-neoplastic effects, either alone or as chelation complexes with various metals. For this study, a small library of ATF compounds was synthesized and tested across a range of microbes, fungi, and cancer cell lines for biological activity, both alone and as metal chelates of copper(I) and silver(I) salts. Alone, the ATF compounds exhibited little antimicrobial activity, but all inhibited the cell growth of A549 lung carcinoma cells (IC50 values of 1-6 µM). As copper(I) and silver(I) coordination complexes, several of the ATFs showed antimicrobial activity against gram positive Staphylococcus aureus and Bacillus subtilis cells (IC50 â¼ 5-20 µM) and the fungi Candida albicans (IC50 â¼ 8-12 µM); as well as cytotoxicity against both lung carcinoma A549 cells and lymphoblastic leukemia K562 cells.
Asunto(s)
Antiinfecciosos , Antineoplásicos , Carcinoma , Complejos de Coordinación , Humanos , Cobre/farmacología , Antiinfecciosos/farmacología , Antiinfecciosos/metabolismo , Plata/farmacología , Línea Celular , Complejos de Coordinación/farmacología , Quelantes/farmacología , Hongos , Pruebas de Sensibilidad Microbiana , Antineoplásicos/farmacología , Antibacterianos/farmacologíaRESUMEN
Two silver(I) complexes with biologically relevant heterocyclic ligands, pyrrole and furan-2- carboxylic acid, were synthesized and their composition was confirmed using elemental, spectral, thermal and structural analyses. The {[Ag(Py2c)]}n (AgPy2c, Py2c = pyrrole-2-carboxylate) and {[Ag(Fu2c)]}n (AgFu2c, Fu2c = furan-2-carboxylate) solubility and stability in biological test stock solution were confirmed by 1H NMR spectroscopy. The X-ray analysis has enabled us to determine typical argentophilic interactions and bridging carboxylate coordination mode of both ligands. Potentiometric data analysis by BSTAC program resulted in the determination of the stability constant of only one species, i.e., the ML (M = Ag+, L = Fu2c-), log ßML = 0.59 ± 0.04. Antimicrobial and anticancer tests were performed against selected microorganisms and cell lines with new silver(I) complexes and compared with AgSD (silver(I) sulfadiazine) and cisplatin. From their microbial toxicity point of view, selectivity was determined against lactobacilli (AgPy2c is 8× more effective against S. aureus and E. coli and AgFu2c is 8× more effective against E. coli and 4× against S. aureus). AgFu2c significant anticancer activity was determined against Jurkat cell lines (IC50 = 8.00 µM) and was similar to cisPt (IC50 = 6.3 µM) similarly to its selectivity (SI (AgFu2c) = 7.3, SI (cisPt) = 6.4, SI = selectivity index). In addition, cell cycle arrest was observed already in the Sub-G0 phase during a flow cytometry experiment. To evaluate the AgPy2c and AgFu2c bioavailability we also discuss their Lipinski's Rule of Five.
Asunto(s)
Antiinfecciosos , Complejos de Coordinación , Plata/farmacología , Plata/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Ligandos , Escherichia coli , Staphylococcus aureus , Antiinfecciosos/farmacología , Antiinfecciosos/química , Furanos/farmacología , Pruebas de Sensibilidad Microbiana , Antibacterianos/farmacología , Antibacterianos/químicaRESUMEN
Complexes of coinage metals can potentially be used as alternatives to platinum-based chemotherapeutic drugs. Silver is a coinage metal that can potentially improve the spectrum of efficacy in various cancers treatment, such as malignant melanoma. Melanoma is the most aggressive form of skin cancer that is often diagnosed in young and middle-aged adults. Silver has high reactivity with skin proteins and can be developed as a malignant melanoma treatment modality. Therefore, this study aims to identify the anti-proliferative and genotoxic effects of silver(I) complexes with mixed-ligands of thiosemicarbazones and diphenyl(p-tolyl)phosphine ligands in the human melanoma SK-MEL-28 cell line. The anti-proliferative effects of a series of silver(I) complex compounds labelled as OHBT, DOHBT, BrOHBT, OHMBT, and BrOHMBT were evaluated on SK-MEL-28 cells by using the Sulforhodamine B assay. Then, DNA damage analysis was performed in a time-dependent manner (30 min, 1 h and 4 h) by using alkaline comet assay to investigate the genotoxicity of OHBT and BrOHMBT at their respective IC50 values. The mode of cell death was studied using Annexin V-FITC/PI flow cytometry assay. Our current findings demonstrated that all silver(I) complex compounds showed good anti-proliferative activity. The IC50 values of OHBT, DOHBT, BrOHBT, OHMBT, and BrOHMBT were 2.38 ± 0.3 µM, 2.70 ± 0.17 µM, 1.34 ± 0.22 µM, 2.82 ± 0.45 µM, and 0.64 ± 0.04 µM respectively. Then, DNA damage analysis showed that OHBT and BrOHMBT could induce DNA strand breaks in a time-dependent manner, with OHBT being more prominent than BrOHMBT. This effect was accompanied by apoptosis induction in SK-MEL-28, as evaluated using Annexin V-FITC/PI assay. In conclusion, silver(I) complexes with mixed-ligands of thiosemicarbazones and diphenyl(p-tolyl)phosphine exerted anti-proliferative activities by inhibiting cancer cell growth, inducing significant DNA damage and ultimately resulting in apoptosis.
Asunto(s)
Melanoma , Tiosemicarbazonas , Adulto , Humanos , Persona de Mediana Edad , Plata , Daño del ADN , Melanoma Cutáneo MalignoRESUMEN
Ag(I) coordination compounds have recently attracted much attention as antiproliferative and antibacterial agents against a wide range of cancer cell lines and pathogens. The bioactivity potential of these complexes depends on their structural characteristics and the nature of their ligands. Herein, we present a series of four Ag(I) coordination compounds bearing as ligands the CH3-substituted thiadiazole-based thioamide 5-methyl-1,3,4-thiadiazole-2-thiol (mtdztH) and phosphines, i.e., [AgCl(mtdztH)(PPh3)2] (1), [Ag(mtdzt)(PPh3)3] (2), [AgCl(mtdztH)(xantphos)] (3), and [AgmtdztH)(dppe)(NO3)]n (4), where xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and dppe = 1,2-bis(diphenylphosphino)ethane, and the assessment of their in vitro antibacterial and anti-cancer efficiency. Among them, diphosphine-containing compounds 3 and 4 were found to exhibit broad-spectrum antibacterial activity characteristics against both Gram-(+) and Gram-(-) bacterial strains, showing high in vitro bioactivity with IC50 values as low as 4.6 µΜ. In vitro cytotoxicity studies against human ovarian, pancreatic, lung, and prostate cancer cell lines revealed the strong cytotoxic potential of 2 and 4, with IC50 values in the range of 3.1-24.0 µΜ, while 3 and 4 maintained the normal fibroblast cells' viability at relatively higher levels. Assessment of these results, in combination with those obtained for analogous Ag(I) complexes bearing similar heterocyclic thioamides, suggest the pivotal role of the substituent groups of the thioamide heterocyclic ring in the antibacterial and anti-cancer efficacy of the respective Ag(I) complexes. Compounds 1-4 exhibited moderate in vitro antioxidant capacity for free radicals scavenging, as well as reasonably strong ability to interact with calf-thymus DNA, suggesting the likely implication of these properties in their bioactivity mechanisms. Complementary insights into the possible mechanism of their anti-cancer activity were provided by molecular docking calculations, exploring their ability to bind to the overexpressed fibroblast growth factor receptor 1 (FGFR1), affecting cancer cells' functionalities.
Asunto(s)
Antineoplásicos , Complejos de Coordinación , Neoplasias , Humanos , Antibacterianos/farmacología , Antibacterianos/química , Antineoplásicos/farmacología , Antineoplásicos/química , Proliferación Celular , Complejos de Coordinación/química , Simulación del Acoplamiento Molecular , Plata/química , Tioamidas/farmacologíaRESUMEN
A series of NHC-based selenourea Ag(I) and Au(I) complexes were evaluated for their anticancer potential inâ vitro, on 2D and 3D human cancer cell systems. All NHC-based selenourea complexes possess an outstanding cytotoxic potency, which was comparable or even better than that of the reference metallodrug auranofin, and were also able to overcome both platinum-based and multi-drug resistances. Intriguingly, their cytotoxic potency did not correlate with solution stability, partition coefficient or cellular uptake. On the other hand, mechanistic studies in cancer cells revealed their ability to strongly and selectively inhibit the redox-regulating enzyme Thioredoxin Reductase (TrxR), being even more effective than auranofin, a well-known TrxR inhibitor, without affecting other redox enzymes such as Glutathione Reductase (GR). The inhibition of TrxR in H157 human cancer cells caused, in turn, the disruption of cellular thiol-redox homeostasis and of mitochondria pathophysiology, ultimately leading to cancer cell death through apoptosis.
Asunto(s)
Antineoplásicos , Neoplasias , Humanos , Reductasa de Tiorredoxina-Disulfuro , Oro , Plata , Auranofina/farmacología , Antineoplásicos/farmacología , Neoplasias/tratamiento farmacológico , Oxidación-Reducción , Homeostasis , Línea Celular TumoralRESUMEN
A family of three- and four-coordinated silver(I) complexes of formulas [Ag(PPh3 )2 L], [Ag(PPh3 )L], and [AgL]n with N-thiophosphorylated thiourea and thioamide ligands of general formula RC(S)NHP(S)(OPri)2 [R = Ph, PhNH, iPrNH, tBuNH, NH2 ] have been studied by solid-state 109 Ag and 31 P CPMAS NMR spectroscopy. 109 Ag NMR spectra have provided valuable structural information about Ag coordination, which is in good accordance with the available crystal structure data. The data presented in this work represent a significant addition to the available 109 Ag chemical shifts and chemical shifts anisotropies. The silver chemical shift ranges for different P,S-environments and coordination state were discussed in detail. The 1 J(31 P-107/109 Ag) and 2 J(31 P-31 P) values were determined and analyzed.
Asunto(s)
Plata , Tiourea , Ligandos , Espectroscopía de Resonancia Magnética/métodos , Plata/química , Tioamidas , Tiourea/químicaRESUMEN
Silver salts and azole derivatives are well known for their antimicrobial properties. Recent evidence has demonstrated also their cytotoxic and genotoxic potential toward both normal and cancer cells. Still, little is known about the action of complexes of azoles with silver(I) salts. Thus, the goal of the study was to compare the chemical, cytotoxic and antimicrobial properties of metronidazole complexes with silver(I) nitrate and silver(I) sulfate to metronidazole and pure silver(I) salts. We synthetized a novel complex, [Ag(MTZ)2]2SO4, and confirmed its chemical structure and properties using 1H and 13C NMR spectroscopy and X-Ray, IR and elemental analysis. To establish the stability of complexes [Ag(MTZ)2NO3] and [Ag(MTZ)2]2SO4, they were exposed to daylight and UV-A rays and were visually assessed. Their cytotoxicity toward human cancer cells (HepG2, Caco-2) and mice normal fibroblasts (Balb/c 3T3 clone A31) was determined by MTT, NRU, TPC and LDH assays. The micro-dilution broth method was used to evaluate their antimicrobial properties against Gram-positive and Gram-negative bacteria. A biofilm eradication study was also performed using the crystal violet method and confocal laser scanning microscopy. The photo-stability of the complexes was higher than silver(I) salts. In human cancer cells, [Ag(MTZ)2]2SO4 was more cytotoxic than Ag2SO4 and, in turn, AgNO3 was more cytotoxic than [Ag(MTZ)2NO3]. For Balb/c 3T3 cells, Ag2SO4 was more cytotoxic than [Ag(MTZ)2]2SO4, while the cytotoxicity of AgNO3 and [Ag(MTZ)2NO3] was similar. Metronidazole in the tested concentration range was non-cytotoxic for both normal and cancer cells. The complexes showed increased bioactivity against aerobic and facultative anaerobic bacteria when compared to metronidazole. For the majority of the tested bacterial strains, the silver(I) salts and complexes showed a higher antibacterial activity than MTZ; however, some bacterial strains presented the reverse effect. Our results showed that silver(I) complexes present higher photo-stability, cytotoxicity and antimicrobial activity in comparison to MTZ and, to a certain extent, to silver(I) salts.
RESUMEN
A series of heteroleptic Ag(I) complexes bearing 4,6-dimethyl-2-pyrimidinethiol (dmp2SH), i.e., [AgCl(dmp2SH)(PPh3)2] (1), [Ag(dmp2SH)(PPh3)2]NO3 (2), [Ag(dmp2SΗ)(xantphos)]NO3 (3), [Ag(µ-dmp2S)(PPh3)]2 (4), [Ag(dmp2S)(xantphos)] (5), [Ag(µ-dmp2S)(DPEphos)]2 (6) (xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and DPEPhos = bis[(2-diphenylphosphino)phenyl]ether) were synthesized. The complexes display systematic variation of particular structural characteristics which were proved to have a significant impact on their in vitro cytotoxicity and antimicrobial properties. A moderate-to-high potential for bacteria growth inhibition was observed for all complexes, with 2, 3 and 5 being particularly effective against Gram-(+) bacteria (IC50 = 1.6-4.5 µM). The three complexes exhibit high in vitro cytotoxicity against HeLa and MCF-7 cancer cells (IC50 = 0.32-3.00 µΜ), suggesting the importance of coordination unsaturation and cationic charge for effective bioactivity. A very low cytotoxicity against HDFa normal cells was observed, revealing a high degree of selectivity (selectivity index ~10) and, hence, biocompatibility. Fluorescence microscopy using 2 showed effective targeting on the membrane of the HeLa cancer cells, subsequently inducing cell death. Binding of the complexes to serum albumin proteins is reasonably strong for potential uptake and subsequent release to target sites. A moderate in vitro antioxidant capacity for free radicals scavenging was observed and a low potential to destroy the double-strand structure of calf-thymus DNA by intercalation, suggesting likely implication of these properties in the bioactivity mechanisms of these complexes. Further insight into possible mechanisms of bioactivity was obtained by molecular modeling calculations, by exploring their ability to act as potential inhibitors of DNA-gyrase, human estrogen receptor alpha, human cyclin-dependent kinase 6, and human papillomavirus E6 oncoprotein.
Asunto(s)
Antiinfecciosos/farmacología , Complejos de Coordinación/química , Plata/química , Tioamidas/química , Antibacterianos/farmacología , Antiinfecciosos/química , Antineoplásicos/farmacología , Antioxidantes/farmacología , Bacterias/efectos de los fármacos , Quinasa 6 Dependiente de la Ciclina/metabolismo , ADN/metabolismo , Girasa de ADN/metabolismo , Células HeLa , Humanos , Ligandos , Células MCF-7 , Pruebas de Sensibilidad Microbiana/métodos , Modelos Moleculares , Simulación del Acoplamiento Molecular/métodos , Fosfinas/química , Plata/farmacología , Tioamidas/farmacología , Xantenos/químicaRESUMEN
We investigated the anti-cancer activity of [Ag(µ-dicl)]n 1 and [AgH(nif)2] 2 complexes against human cancer cell lines (MCF-7, HT-29, and HepG2) and mouse fibroblast (3T3-L1) cell line. Anti-proliferative activity was monitored by XTT cell viability and LDH leakage assays. Cell death mode was evaluated by multi-caspase activity, annexin V cytofluorimetric, MMP, cell cycle arrest, and ROS generation assays. Antioxidant capacity was evaluated on SOD, GPx, GR, and CAT enzymes. The XTT and LDH assay results showed that both complexes exhibited strong cytotoxicity against the tested cancer cell lines. The apoptotic mechanisms of the complexes were demonstrated by loss of MMP and increase in phosphatidylserine translocation, sub-G1 phase, and multi-caspase activity. Besides, both complexes induced the oxidative stress in MCF-7 cells by decreasing the activity of GPx, GR, and CAT enzymes. In conclusion, both Ag(I) complexes, especially 1, warrant for further in vivo evaluation as a new alternative in cancer treatment.HighlightsAg(I) complexes inhibited cell proliferation and induced LDH leakage in human cancer cell lines.Ag(I) complexes induced apoptosis through MMP disruption and ROS generation.Ag(I) complexes mimicked the multi-caspase activity.Ag(I) complexes increased the accumulation of sub-G1 phase.Ag(I) complexes inhibited the activity of antioxidant system enzymes.
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Neoplasias , Plata , Animales , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Diclofenaco , Humanos , Células MCF-7 , Ratones , Ácido Niflúmico , Especies Reactivas de OxígenoRESUMEN
Three silver(I) dipeptide complexes [Ag(GlyGly)]n(NO3)n (AgGlyGly), [Ag2(GlyAla)(NO3)2]n (AgGlyAla) and [Ag2(HGlyAsp)(NO3)]n (AgGlyAsp) were prepared, investigated and characterized by vibrational spectroscopy (mid-IR), elemental and thermogravimetric analysis and mass spectrometry. For AgGlyGly, X-ray crystallography was also performed. Their stability in biological testing media was verified by time-dependent NMR measurements. Their in vitro antimicrobial activity was evaluated against selected pathogenic microorganisms. Moreover, the influence of silver(I) dipeptide complexes on microbial film formation was described. Further, the cytotoxicity of the complexes against selected cancer cells (BLM, MDA-MB-231, HeLa, HCT116, MCF-7 and Jurkat) and fibroblasts (BJ-5ta) using a colorimetric MTS assay was tested, and the selectivity index (SI) was identified. The mechanism of action of Ag(I) dipeptide complexes was elucidated and discussed by the study in terms of their binding affinity toward the CT DNA, the ability to cleave the DNA and the ability to influence numbers of cells within each cell cycle phase. The new silver(I) dipeptide complexes are able to bind into DNA by noncovalent interaction, and the topoisomerase I inhibition study showed that the studied complexes inhibit its activity at a concentration of 15 µM.
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Antiinfecciosos/química , Antiinfecciosos/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Dipéptidos/química , Plata/química , Antiinfecciosos/síntesis química , Antineoplásicos/síntesis química , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Fenómenos Químicos , Técnicas de Química Sintética , Complejos de Coordinación/síntesis química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Estabilidad de Medicamentos , Humanos , Conformación Molecular , Simulación de Dinámica Molecular , Análisis Espectral , Relación Estructura-Actividad , TermogravimetríaRESUMEN
The reaction of the antitumor M(I)-bis-N-heterocyclic carbene (M(I)-NHC) complexes, M = Cu, Ag, and Au, with their potential protein binding sites, i.e. cysteine and selenocysteine, was investigated by means of density functional theory approaches. Capped cysteine and selenocysteine were employed to better model the corresponding residues environment within peptide structures. By assuming the neutral or deprotonated form of the side chains of these amino acids and by considering the possible assistance of an external proton donor such as an adjacent acidic residue or the acidic component of the surrounding buffer environment, we devised five possible routes leading to the binding of the investigated M(I)-NHC scaffolds to these protein sites, reflecting their different location in the protein structure and exposure to the bulk. The targeting of either cysteine or selenocysteine in their neutral forms is a kinetically unfavored process, expected to be quite slow if observable at all at physiological temperature. On the other hand, the reaction with the deprotonated forms is much more favored, even though an external proton source is required to assist the protonation of the leaving carbene. Our calculations also show that all coinage metals are characterized by a similar reactivity toward the binding of cysteine and selenocysteine sites, although the Au(I) complex has significantly higher reaction and activation free energies compared to Cu(I) and Ag(I).
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Antineoplásicos/química , Complejos de Coordinación/química , Cisteína/química , Selenocisteína/química , Cobre/química , Teoría Funcional de la Densidad , Oro/química , Ligandos , Modelos Químicos , Estructura Molecular , Plata/química , TermodinámicaRESUMEN
BACKGROUND: Silver is a transition metal that is known to be less toxic than platinum. However, only few studies have reported the anticancer effects of some silver complexes and their possibility as an alternative to platinum complex. This study investigated the anticancer effects of the silver thiosulfate complex (STS), [Ag(S2O3)2]3-, consisting of silver and sodium thiosulfate. METHODS: In vitro cytotoxic activity of STS was investigated comparatively in human cancer cell lines (K562 and MCF-7) and normal human cells (mesenchymal stem cells and mammary epithelial cells). For its anticancer effects, cell cycle, mode of cell death, morphological changes, and accumulation of intracellular ROS and GSH were evaluated in MCF-7 to provide mechanistic insights. RESULTS: STS showed a concentration-dependent cytotoxicity in MCF-7 cell, which was abolished by pretreatment with N-acetylcysteine, suggesting ROS accumulation by STS. Moreover, STS caused cell cycle arrest at the G1 phase, decrease in the GSH levels, and morphological changes in MCF-7. Direct measurement of ROS demonstrated the elevation of intracellular ROS accumulation in cancer cells treated with STS; however, neither cytotoxicity nor ROS accumulation was observed in normal human cells. CONCLUSION: The results obtained here are the first evidence to show that STS exhibited an anticancer activity through ROS-induced mechanisms, and that its cytotoxicity is highly selective to cancer cells. The results of the present study warrant further investigation on the detailed mechanism of STS actions, as well as its in vivo effectiveness and safety for clinical application.
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Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Muerte Celular/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Plata/farmacología , Tiosulfatos/farmacología , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Femenino , Fase G1/efectos de los fármacos , Humanos , Células K562 , Células MCF-7RESUMEN
Three new silver(I) complexes [Ag(NO3)(tia)(H2O)]n (Ag1), [Ag(CF3SO3)(1,8-naph)]n (Ag2) and [Ag2(1,8-naph)2(H2O)1.2](PF6)2 (Ag3), where tia is thianthrene and 1,8-naph is 1,8-naphthyridine, were synthesized and structurally characterized by different spectroscopic and electrochemical methods and their crystal structures were determined by single-crystal X-ray diffraction analysis. Their antimicrobial potential was evaluated against four bacterial and three Candida species, and the obtained results revealed that these complexes showed significant activity toward the Gram-positive Staphylococcus aureus, Gram-negative Pseudomonas aeruginosa and the investigated Candida species with minimal inhibitory concentration (MIC) values in the range 1.56-7.81 µg/mL. On the other hand, tia and 1,8-naph ligands were not active against the investigated strains, suggesting that their complexation with Ag(I) ion results in the formation of antimicrobial compounds. Moreover, low toxicity of the complexes was detected by in vivo model Caenorhabditis elegans. The interaction of the complexes with calf thymus DNA (ct-DNA) and bovine serum albumin (BSA) was studied to evaluate their binding affinity towards these biomolecules for possible insights into the mode of antimicrobial activity. The binding affinity of Ag1-3 to BSA was higher than that for DNA, indicating that proteins could be more favorable binding sites for these complexes in comparison to the nucleic acids.
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Antiinfecciosos , Complejos de Coordinación , Compuestos Heterocíclicos/química , Naftiridinas/química , Plata/química , Animales , Antiinfecciosos/química , Antiinfecciosos/metabolismo , Antiinfecciosos/farmacología , Bacterias/efectos de los fármacos , Caenorhabditis elegans/efectos de los fármacos , Candida/efectos de los fármacos , Complejos de Coordinación/química , Complejos de Coordinación/metabolismo , Complejos de Coordinación/farmacología , ADN/metabolismo , Estructura Molecular , Unión Proteica , Albúmina Sérica Bovina/metabolismoRESUMEN
In a previous article, we reported on the higher toxicity of silver(I) complexes of miconazole [Ag(MCZ)2NO3 (1)] and [Ag(MCZ)2ClO4 (2)] in HepG2 tumor cells compared to the corresponding salts of silver, miconazole and cisplatin. Here, we present the synthesis of two silver(I) complexes of miconazole containing two new counter ions in the form of Ag(MCZ)2X (MCZ = 1-[2-(2,4-dichlorobenzyloxy)-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole]; X = BF4- (3), SbF6- (4)). The novel silver(I) complexes were characterized by elemental analysis, 1H NMR, 13C NMR and infrared (IR) spectroscopy, electrospray ionization (ESI)-MS spectrometry and X-ray-crystallography. In the present study, the antimicrobial activity of all obtained silver(I) complexes of miconazole against six strains of Gram-positive bacteria, five strains of Gram-negative bacteria and yeasts was evaluated. The results were compared with those of a silver sulfadiazine drug, the corresponding silver salts and the free ligand. Silver(I) complexes exhibited significant activity against Gram-positive bacteria, which was much better than that of silver sulfadiazine and silver salts. The highest antimicrobial activity was observed for the complex containing the nitrate counter ion. All Ag(I) complexes of miconazole resulted in much better inhibition of yeast growth than silver sulfadiazine, silver salts and miconazole. Moreover, the synthesized silver(I) complexes showed good or moderate activity against Gram-negative bacteria compared to the free ligand.