RESUMO
The reaction of the Ru(PPh3 )3 Cl2 with HL1-3 -OH (-OH stands for the oxime hydroxyl group; HL1 -OH=diacetylmonoxime-S-benzyldithiocarbazonate; HL2 -OH=diacetylmonoxime-S-(4-methyl)benzyldithiocarbazonate; and HL3 -OH=diacetylmonoxime-S-(4-chloro)benzyl-dithiocarbazonate) gives three new ruthenium complexes [RuII (L1-3 -H)(PPh3 )2 Cl] (1-3) (-H stands for imine hydrogen) coordinated with dithiocarbazate imine as the final products. All ruthenium(II) complexes (1-3) have been characterized by elemental (CHNS) analyses, IR, UV-vis, NMR (1 H, 13 C, and 31 P) spectroscopy, HR-ESI-MS spectrometry and also, the structure of 1-2 was further confirmed by single crystal X-ray crystallography. The solution/aqueous stability, hydrophobicity, DNA interactions, and cell viability studies of 1-3 against HeLa, HT-29, and NIH-3T3â cell lines were performed. Cell viability results suggested 3 being the most cytotoxic of the series with IC50 6.9±0.2â µM against HeLa cells. Further, an apoptotic mechanism of cell death was confirmed by cell cycle analysis and Annexin V-FITC/PI double staining techniques. In this regard, the live cell confocal microscopy results revealed that compounds primarily target the mitochondria against HeLa, and HT-29â cell lines. Moreover, these ruthenium complexes elevate the ROS level by inducing mitochondria targeting apoptotic cell death.
Assuntos
Antineoplásicos , Complexos de Coordenação , Rutênio , Humanos , Células HeLa , Rutênio/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Apoptose , Iminas , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Linhagem Celular TumoralRESUMO
The transport and cytotoxicity of molybdenum-based drugs have been explained with the concept of chemical transformation, a very important idea in inorganic medicinal chemistry that is often overlooked in the interpretation of the biological activity of metal-containing systems. Two monomeric, [MoO2(L1)(MeOH)] (1) and [MoO2(L2)(EtOH)] (2), and two mixed-ligand dimeric MoVIO2 species, [{MoO2(L1-2)}2(µ-4,4'-bipy)] (3-4), were synthesized and characterized. The structures of the solid complexes were solved through SC-XRD, while their transformation in water was clarified by UV-vis, ESI-MS, and DFT. In aqueous solution, 1-4 lead to the penta-coordinated [MoO2(L1-2)] active species after the release of the solvent molecule (1 and 2) or removal of the 4,4'-bipy bridge (3 and 4). [MoO2(L1-2)] are stable in solution and react with neither serum bioligand nor cellular reductants. The binding affinity of 1-4 toward HSA and DNA were evaluated through analytical and computational methods and in both cases a non-covalent interaction is expected. Furthermore, the in vitro cytotoxicity of the complexes was also determined and flow cytometry analysis showed the apoptotic death of the cancer cells. Interestingly, µ-4,4'-bipy bridged complexes 3 and 4 were found to be more active than monomeric 1 and 2, due to the mixture of species generated, that is [MoO2(L1-2)] and the cytotoxic 4,4'-bipy released after their dissociation. Since in the cytosol neither the reduction of MoVI to MoV/IV takes place nor the production of reactive oxygen species (ROS) through Fenton-like reactions of 1-4 with H2O2 occurs, the mechanism of cytotoxicity should be attributable to the direct interaction with DNA that happens with a minor-groove binding which results in cell death through an apoptotic mechanism.
Assuntos
Peróxido de Hidrogênio , Molibdênio , DNA/química , Ligantes , Molibdênio/química , Molibdênio/farmacologia , Água/químicaRESUMO
Five new anionic aqueous dioxidovanadium(V) complexes, [{VO2L1,2}A(H2O)n]α (1-5), with the aroylhydrazone ligands pyridine-4-carboxylic acid (3-ethoxy-2-hydroxybenzylidene)hydrazide (H2L1) and furan-2-carboxylic acid (3-ethoxy-2-hydroxybenzylidene)hydrazide (H2L2) incorporating different alkali metals (A = Na+, K+, Cs+) as countercation were synthesized and characterized by various physicochemical techniques. The solution-phase stabilities of 1-5 were determined by time-dependent NMR and UV-vis, and also the octanol/water partition coefficients were obtained by spectroscopic techniques. X-ray crystallography of 2-4 confirmed the presence of vanadium(V) centers coordinated by two cis-oxido-O atoms and the O, N, and O atoms of a dianionic tridentate ligand. To evaluate the biological behavior, all complexes were screened for their DNA/protein binding propensity through spectroscopic experiments. Finally, a cytotoxicity study of 1-5 was performed against colon (HT-29), breast (MCF-7), and cervical (HeLa) cancer cell lines and a noncancerous NIH-3T3 cell line. The cytotoxicity was cell-selective, being more active against HT-29 than against other cells. In addition, the role of hydrophobicity in the cytotoxicity was explained in that an optimal hydrophobicity is essential for high cytotoxicity. Moreover, the results of wound-healing assays indicated antimigration in case of HT-29 cells. Remarkably, 1 with an IC50 value of 5.42 ± 0.15 µM showed greater activity in comparison to cisplatin against the HT-29 cell line.
Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , DNA/química , Hidrazonas/farmacologia , Soroalbumina Bovina/química , Compostos de Vanádio/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidrazonas/química , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Modelos Moleculares , Estrutura Molecular , Células NIH 3T3 , Solubilidade , Compostos de Vanádio/química , Água/químicaRESUMO
The reaction of 2-{2-(benzo[1,3]dioxol-5-yl)- diazo}-4-methylphenol (HL) with [Ru(PPh3)3Cl2] in ethanol resulted in the carbonylated ruthenium complex [RuL(PPh3)2(CO)] (1), wherein metal-assisted decarbonylation via in situ ethanol dehydrogenation is observed. When the reaction was performed in acetonitrile, however, the complex [RuL(PPh3)2(CH3CN)] (2) was obtained as the main product, probably by trapping of a common intermediate through coordination of CH3CN to the Ru(II) center. The analogous reaction of HL with [Ir(PPh3)3Cl] in ethanol did not result in ethanol decarbonylation and instead gave the organoiridium hydride complex [IrL(PPh3)2(H)] (3). Unambiguous evidence for the generation of CO via ruthenium-assisted ethanol oxidation is provided by the synthesis of the 13C-labeled complex, [Ru(PPh3)2L(13CO)] (1A) using isotopically labeled ethanol, CH313CH2OH. To summarize all the evidence, a ruthenium-assisted mechanistic pathway for the decarbonylation and generation of alkane via alcohol dehydrogenation is proposed. In addition, the in vitro antiproliferative activity of complexes 1-3 was tested against human cervical (HeLa) and human colorectal adenocarcinoma (HT-29) cell lines. Complexes 1-3 showed impressive cytotoxicity against both HeLa (half-maximal inhibitory concentration (IC50) value of 3.84-4.22 µM) and HT-29 cancer cells (IC50 values between 3.3 and 4.5 µM). Moreover, the complexes were comparatively less toxic to noncancerous NIH-3T3 cells.
Assuntos
Antineoplásicos/farmacologia , Monóxido de Carbono/síntese química , Complexos de Coordenação/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Isótopos de Carbono/química , Catálise , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/toxicidade , Ensaios de Seleção de Medicamentos Antitumorais , Etanol/química , Humanos , Irídio/química , Marcação por Isótopo , Camundongos , Células NIH 3T3 , Oxirredução , Rutênio/químicaRESUMO
Two new mononuclear cobalt(II) complexes with the general formula [Co(L1,2)2] (1 and 2) were synthesized using bidentate Schiff base ligands with NO donor set, namely, 2-(benzothiazole-2-ylimino)methyl-5-(diethylamino)phenol (HL1) and its methyl substituted derivative 2-(6-methylbenzothiazole-2-ylimino)methyl-5-(diethylamino)phenol (HL2). X-ray structure analysis reveals a distorted pseudotetrahedral coordination sphere at the cobalt(II) ion, that cannot be described by a simple twisting of the two ligand chelate planes with respect to each other, which would imply a rotation about the pseudo-S4 axis of the complex. Such a pseudo-rotation axis would approximately be colinear with the two vectors defined by the cobalt ion and the two centroids of the chelate ligands, where the angle κ between the two vectors would be 180° in an ideal pseudotetrahedral arrangement. For complexes 1 and 2, the observed distortion can be characterized by a significant bending at the cobalt ion with angles κ of 163.2° and 167.4°, respectively. Magnetic susceptibility and FD-FT THz-EPR measurements together with ab initio calculations reveal an easy-axis type of anisotropy for both complexes 1 and 2, with a spin-reversal barrier of 58.9 and 60.5 cm-1, respectively. For both compounds, frequency-dependent ac susceptibility measurements show an out-of-phase susceptibility under applied static fields of 40 and 100 mT, which can be analyzed in terms of Orbach and Raman processes within the observed temperature range.
RESUMO
In this work, one oxidomethoxidovanadium(V) [VVO(L)(OMe)] (1) and two mixed-ligand oxidovanadium(IV) [VIVO(L)(phen)] (2), and [VIVO(L)(bipy)] (3) complexes have been synthesized using a tridentate bi-negative ONS donor dithiocarbazate as main ligand, H2L [where, H2L = S-benzyl-3-(2-hydroxy-3-ethoxyphenyl)methylenedithiocarbazate] along with 1,10-phenanthroline (phen) (for 2) and 2,2'-bipyridine (bipy) (for 3) as co-ligands. The ligand and complexes have been characterised by FT-IR, UV-vis, NMR, and HR-ESI-MS techniques. Distorted square pyramidal for 1, and distorted octahedral geometry for 2 and 3 was confirmed by single crystal X-ray crystallography. The behavior of 1-3 in solution medium has been investigated through various physicochemical techniques. It is observed that 1 completely and 2-3 partially decomposes and converts into a penta-coordinated species, [VIVO(L)(DMSO/H2O)] after the release of the methoxido group (1) or breaking of the diimine based co-ligands (2 and 3) in DMSO/aqueous solution. Interestingly, in DMSO/aqueous solution, 1 gets completely reduced and converted into the corresponding oxidovanadium(IV) species. Interaction of 1-3 with calf thymus DNA (CT-DNA) was investigated and the results show, complex 2 exhibited the maximum binding constants, Kb = 7.12 × 104 M-1. The anticancer potential of 1-3 was evaluated by cell viability assay against human breast carcinoma cell, MCF-7, and noncancerous mouse embryonic cell, NIH-3T3 and 2 was found to be the most cytotoxic complex (IC50 = 6.73 ± 0.36 µM) in the series. In addition, 2 selectively inhibit colony formation compared to the rest complexes. Also, the cell cycle studies of the complexes were performed using flow cytometry analysis.
Assuntos
Complexos de Coordenação , Dimetil Sulfóxido , Animais , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Cristalografia por Raios X , DNA/química , Ligantes , Camundongos , Fenantrolinas/química , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
Herein we report the synthesis of five new mononuclear mixed ligand oxidovanadium(IV) complexes [VIVO(L1-3)(LNN)] (1-5) with tridentate O,N,O-donor aroylhydrazones as main ligand (H2L1-3) and N,N-chelating 2,2'-bipyridine (bipy) and 1,10-phenanthroline (phen) as co-ligand (LNN). The complexes were characterized by elemental and thermogravimetric analysis (TGA), IR, UV-vis, and electron paramagnetic resonance (EPR) spectroscopy, electrospray ionization-mass spectrometry (ESI-MS) and cyclic voltammetry (CV). The structure of 1-5 was confirmed by single crystal X-ray analysis and also optimized by density functional theory (DFT) methods. At physiological pH an equilibrium [VIVO(L1-3)(LNN)] + H2O â [VIVO(L1-3)(H2O)] + LNN, shifted towards left, is established, with water molecule that could be replaced by the biomolecules of the organism. The studies on the interaction with two proteins, lysozyme (Lyz) chosen as a representative model of a small protein, and human serum albumin (HSA) show that two types of binding are possible: a non-covalent binding through the accessible residues on protein surface with [VIVO(L1-3)(LNN)] keeping its octahedral structure, and a covalent binding upon the replacement of water in [VIVO(L1-3)(H2O)] with His-N donors to form VIVO(L1-3)(HSA). In vitro cytotoxicity of ligands and complexes were screened against human cervical cancer (HeLa) (IC50 = 7.39-15.13 µM), colon cancer (HT-29) (IC50 = 11.04-28.20 µM) and mouse embryonic fibroblast (NIH-3T3) cell lines (IC50 = 62.22-87.75 µM) by MTT assay. Particularly, 5 showed higher cytotoxicity than cisplatin and cyclophosphamide, with an IC50 of 7.39 ± 1.21 µM and 11.04 ± 0.29 µM against HeLa and HT-29.
Assuntos
Complexos de Coordenação , Animais , Complexos de Coordenação/química , Fibroblastos , Humanos , Ligantes , Camundongos , Albumina Sérica Humana/química , ÁguaRESUMO
Two new µ2-oxido bridged divanadium (V) complexes, [VV2O3(L1,2)2] (1 and 2) have been synthesized using bi-negative tridentate ONO-donor ligands, H2L1,2 (H2L1 = 4-tert-butyl-2-[[[3,5-di-tert-butyl-2-hydroxyphenyl]methylene]amino]phenol and H2L2 = 5-bromo-2-[[[4-(diethylamino)-2-hydroxyphenyl]methylene]amino]phenol). The synthesized ligands and complexes have been characterized through FT-IR, UV-vis, NMR, and HR-ESI-MS techniques. Single crystal X-ray crystallography data confirmed distorted square pyramidal geometry for both the complexes. The aqueous phase stability of these complexes has been evaluated through HR-ESI-MS in CH3CN:H2O (80:20) mixture. Thereafter their interaction with calf thymus DNA (CT-DNA) have been studied using electronic absorption and fluorescence spectroscopy, revealing an intercalation mode of binding, with binding constant in the order of 104 M-1. Moreover, bovine serum albumin (BSA) interaction of 1 and 2 has been evaluated via fluorescence quenching experiment, which suggests that the quenching mechanism is static (~1013 M-1) in nature. Additionally, the in vitro cytotoxicity of the complexes has been evaluated in human cervical cancer cells (HeLa) (IC50 = 13.57-16.62 µM) and normal mouse embryonic fibroblasts cells (NIH-3T3). The mechanism of cell death brought about by these complexes was studied by nuclear staining, cell cycle and Annexin V/PI double staining apoptotic assay. These studies indicate that 1 and 2 exert inhibitory effects on the S and G2M phase of cell cycle, which is an indication of apoptotic cell death. Also, a clonogenic assay was performed, which showed that the complexes could effectively inhibit colony formation.
Assuntos
Antineoplásicos , Complexos de Coordenação , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Complexos de Coordenação/química , Cristalografia por Raios X , DNA/química , Fibroblastos/metabolismo , Humanos , Ligantes , Camundongos , Fenóis , Ligação Proteica , Soroalbumina Bovina/química , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
A unique C2 symmetric azine bridged bi-ferrocenyl receptor (4) has been modelled and synthesized. In this work, we are able to synthetically regulate conjugation of the dibenzylidenehydrazine fluorophore unit to unexpectedly reveal metal-coordination driven intramolecular twisting. The present probe shows a dramatic turn-on fluorescence response with 91 fold increment of quantum yield along with 17 nm blue shift upon binding with Hg2+ ions selectively with a limit of detection as low as 15 nM. Upon Hg2+ recognition, the ferrocene/ferrocinium redox peak was anodically shifted by ΔE1/2 = 78 mV, indicating the formation of a new complex species. A plausible binding mode of Hg2+ ions with compound 4 has been proposed based on 1H NMR titration, a high-resolution mass spectrometry (HRMS) study and a density functional theory (DFT) study along with the Job's plot analysis. Interestingly, DFT calculations have revealed that the reason for fluorescence enhancement after coordination to Hg2+ ions is not due to conventional restricted C[double bond, length as m-dash]N isomerization or interrupted N-N single bond rotation rather it is due to the increase of the π â π* transition at the expense of the n â π* (aromatic) transition of the free ligand. Furthermore, TD-DFT calculations of the first excited singlet state of 4 and [4·Hg2+] revealed the involvement of the aromatic π electrons with the vacant site of Hg2+ ions which may be further attributed to the fluorescence enhancement phenomenon. In addition, receptor 4 was successfully applied for the detection of Hg2+ ions in real samples.