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1.
Gene ; 763: 144997, 2020 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-32783992

RESUMO

The CRISPR-Cas system currently stands as one of the best multifaceted tools for site-specific genome engineering in mammals. An important aspect of research in this field focusses on improving the specificity and efficacy of precise genome editing in multiple model systems. The cornerstone of this mini-review is one of the extensively investigated small molecule inhibitor, SCR7, which abrogates NHEJ, a Ligase IV-dependent DSB repair pathway, thus guiding integration of the foreign DNA fragment via the more precise homology directed repair during genome editing. One of our recent studies sheds light on properties of different forms of SCR7. Here, we give a succinct account on the use of SCR7 and its different forms in CRISPR-Cas system, highlighting their chemical properties and biological relevance as potent efficiency-enhancing CRISPR tools.


Assuntos
Sistemas CRISPR-Cas , Inibidores Enzimáticos/farmacologia , Edição de Genes/métodos , Pirimidinas/farmacologia , Reparo de DNA por Recombinação/efeitos dos fármacos , Bases de Schiff/farmacologia , Animais , DNA Ligase Dependente de ATP/antagonistas & inibidores , Inibidores Enzimáticos/química , Humanos , Pirimidinas/química , Bases de Schiff/química
2.
PLoS One ; 15(4): e0231147, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32287324

RESUMO

This paper reports the synthesis, characterization, anticancer screening and quantum chemical calculation of a tetradentate Schiff base 2,2'-((1E,1'E)-((2,2-dimethylpropane-1,3-diyl)bis- (azanylylidene))bis(methanylylidene))bis(4-fluorophenol) (L2F) and its Pd (II) complex (PdL2F). The compounds were characterized via UV-Visible, NMR, IR spectroscopy and single crystal x-ray diffraction. Density Functional Theory (DFT) and time-dependent DFT calculations in gas and solvent phases were carried out using B3LYP, B3P86, CAM-B3LYP and PBE0 hybrid functionals combined with LanL2DZ basis set. Complexation of L2F to form PdL2F was observed to cause a bathochromic shift of the maximum absorption bands of n-π* from 327 to 410 nm; an upfield shift for δ (HC = N) from 8.30 to 7.96 ppm and a decreased wavenumber for ν(C = N) from 1637 to 1616 cm-1. Overall, the UV-Vis, NMR and IR spectral data are relatively well reproduced through DFT and TD-DFT methods. L2F and PdL2F showed IC50 of 90.00 and 4.10 µg/mL, respectively, against human colorectal carcinoma (HCT116) cell lines, signifying increased anticancer activity upon complexation with Pd (II).


Assuntos
Complexos de Coordenação/farmacologia , Paládio/farmacologia , Bases de Schiff/farmacologia , Técnicas de Química Sintética/métodos , Complexos de Coordenação/química , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Concentração Inibidora 50 , Ligantes , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Paládio/química , Bases de Schiff/química , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier
3.
Mol Carcinog ; 59(6): 618-628, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32189406

RESUMO

Targeting DNA repair with small-molecule inhibitors is an attractive strategy for cancer therapy. Majority of DNA double-strand breaks in mammalian cells are repaired through nonhomologous end-joining (NHEJ). It has been shown that small-molecule inhibitors of NHEJ can block efficient repair inside cancer cells, leading to cell death. Previously, we have reported that SCR7, an inhibitor of NHEJ can induce tumor regression in mice. Later studies have shown that different forms of SCR7 can inhibit DNA end-joining in Ligase IV-dependent manner. Recently, we have derivatized SCR7 by introducing spiro ring into core structure. Here, we report the identification of a novel inhibitor of NHEJ, named SCR130 with 20-fold higher efficacy in inducing cytotoxicity in cancer cell lines. SCR130 inhibited DNA end-joining catalyzed by rat tissue extract. Specificity analysis revealed that while SCR130 was specific to Ligase IV, it showed minimal or no effect on Ligase III and Ligase I mediated joining. Importantly, SCR130 exhibited the least cytotoxicity in Ligase IV-null cell line as compared with wild type, confirming Ligase IV-specificity. Furthermore, we demonstrate that SCR130 can potentiate the effect of radiation in cancer cells when used in combination with γ-radiation. Various cellular assays in conjunction with Western blot analysis revealed that treatment with SCR130 led to loss of mitochondrial membrane potential leading to cell death by activating both intrinsic and extrinsic pathways of apoptosis. Thus, we describe a novel inhibitor of NHEJ with higher efficacy and may have the potential to be developed as cancer therapeutic.


Assuntos
Antineoplásicos/farmacologia , Morte Celular , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Reparo do DNA por Junção de Extremidades/efeitos dos fármacos , DNA Ligase Dependente de ATP/antagonistas & inibidores , Pirimidinas/farmacologia , Bases de Schiff/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Células HeLa , Humanos , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Ratos
4.
Eur J Med Chem ; 193: 112234, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32213395

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common cancers and a leading cause of death worldwide. Increased thioredoxin reductase (TrxR) levels were recently identified as possible prognostic markers for HCC. Here, four gold(III) complexes 1b-4b bearing Schiff base ligands were synthesized, characterized, and screened for antitumor activity against HCC. All complexes triggered significant antiproliferative effects against HCC cells, especially the most active complex 1b induced HepG2 cells apoptosis by activating the endoplasmic reticulum stress (ERS). 1b could clearly inhibit the TrxR activity to elevate reactive oxygen species (ROS), mediate ERS and lead to mitochondrial dysfunction. Notably, treatment of 1b improved the CCl4-induced liver damage in vivo by down-regulation of TrxR expression and inflammation level.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Ouro/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ouro/química , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Modelos Moleculares , Estrutura Molecular , Espécies Reativas de Oxigênio/metabolismo , Bases de Schiff/química , Bases de Schiff/farmacologia , Relação Estrutura-Atividade , Tiorredoxina Dissulfeto Redutase/genética , Tiorredoxina Dissulfeto Redutase/metabolismo
5.
Dalton Trans ; 49(15): 4843-4860, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32219227

RESUMO

We have prepared six new nickel Schiff base complexes via reactions of substituted benzophenones with different diamines in the presence of nickel(ii). These new complexes were then reacted with 1-(2-choroethyl)piperidine to afford a further six novel nickel(ii) Schiff base complexes bearing pendant ethylpiperidine groups. The complexes bearing the ethylpiperidine moieties had greater solubility in water, and were therefore suitable for use in DNA binding experiments. ESI mass spectra of solutions containing 4 and the parallel, tetramolecular quadruplex Q4, contained ions attributable to formation of non-covalent complexes. In contrast, no ions from non-covalent complexes were observed when the experiments were repeated using 4 and either a double stranded DNA (dsDNA) molecule (D2), or parallel Q1, a unimolecular quadruplex DNA (qDNA). The ESI-MS binding study also revealed that 14 has a significant ability to form non-covalent complexes with qDNA, but does not interact to the same extent with D2. This is supported by the large changes to the ellipticity of bands observed in the circular dichroism spectra of two different unimolecular qDNA molecules (c-kit1 and Q1), including the latter annealed under conditions designed to induce formation of alternative topologies (antiparallel and hybrid). In Fluorescent Indicator Displacement (FID) assays conducted using the new nickel complexes, 14 gave the lowest values of DC50 for experiments conducted with Q1 and Q4. Furthermore, 14 showed greater stabilisation of an antiparallel qDNA molecule in FRET assays than when the other new complexes were examined. These results highlight the potential of 14 as a lead complex for future structure/DNA binding investigations. This is reinforced by the results obtained from cytotoxicity studies performed using four of the nickel complexes, including 14, and Chinese hamster lung cancer (V79) cells, which gave IC50 values between 4 and 12 µM. These complexes were also shown to have the ability to induce apoptosis in the same cancer cell line.


Assuntos
Complexos de Coordenação/química , Quadruplex G , Níquel/química , Animais , Apoptose/efeitos dos fármacos , Benzofenonas/química , Benzofenonas/farmacologia , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Cricetulus , DNA/química , Diaminas/química , Diaminas/farmacologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Níquel/farmacologia , Bases de Schiff/química , Bases de Schiff/farmacologia
7.
Acta Crystallogr C Struct Chem ; 76(Pt 1): 44-63, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31919307

RESUMO

Eight novel Schiff bases derived from benzil dihydrazone (BDH) or benzil monohydrazone (BMH) and four fused-ring carbonyl compounds (3-formylindole, FI; 3-acetylindole, AI; 3-formyl-1-methylindole, MFI; 1-formylnaphthalene, FN) were synthesized and characterized by elemental analysis, ESI-QTOF-MS, 1H and 13C NMR spectroscopy, as well as single-crystal X-ray diffraction. They are (1Z,2Z)-1,2-bis{(E)-[(1H-indol-3-yl)methylidene]hydrazinylidene}-1,2-diphenylethane (BDHFI), C32H24N6, (1Z,2Z)-1,2-bis{(E)-[1-(1H-indol-3-yl)ethylidene]hydrazinylidene}-1,2-diphenylethane (BDHAI), C34H28N6, (1Z,2Z)-1,2-bis{(E)-[(1-methyl-1H-indol-3-yl)methylidene]hydrazinylidene}-1,2-diphenylethane (BMHMFI) acetonitrile hemisolvate, C34H28N6·0.5CH3CN, (1Z,2Z)-1,2-bis{(E)-[(naphthalen-1-yl)methylidene]hydrazinylidene}-1,2-diphenylethane (BDHFN), C36H26N4, (Z)-2-{(E)-[(1H-indol-3-yl)methylidene]hydrazinylidene}-1,2-diphenylethanone (BMHFI), C23H17N3O, (Z)-2-{(E)-[1-(1H-indol-3-yl)ethylidene]hydrazinylidene}-1,2-diphenylethanone (BMHAI), C24H19N3O, (Z)-2-{(E)-[(1-methyl-1H-indol-3-yl)methylidene]hydrazinylidene}-1,2-diphenylethanone (BMHMFI), C24H19N3O, and (Z)-2-{(E)-[(naphthalen-1-yl)methylidene]hydrazinylidene}-1,2-diphenylethanone (BMHFN) C25H18N2O. Moreover, the in vitro cytotoxicity of the eight title compounds was evaluated against two tumour cell lines (A549 human lung cancer and 4T1 mouse breast cancer) and two normal cell lines (MRC-5 normal lung cells and NIH 3T3 fibroblasts) by MTT assay. The results indicate that four (BDHMFI, BDHFN, BMHMFI and BMHFN) are inactive and the other four (BDHFI, BDHAI, BMHFI and BMHAI) show severe toxicities against human A549 and mouse 4T1 cells, similar to the standard cisplatin. All the compounds exhibited weaker cytotoxicity against normal cells than cancer cells. The Swiss Target Prediction web server was applied for the prediction of protein targets. After analyzing the differences in frequency hits between these active and inactive Schiff bases, 18 probable targets were selected for reverse docking with the Surflex-dock function in SYBYL-X 2.0 software. Three target proteins, i.e. human ether-á-go-go-related (hERG) potassium channel, the inhibitor of apoptosis protein 3 and serine/threonine-protein kinase PIM1, were chosen as the targets. Finally, the ligand-based structure-activity relationships were analyzed based on the putative protein target (hERG) docking results, which will be used to design and synthesize novel hERG ion channel inhibitors.


Assuntos
Proliferação de Células/efeitos dos fármacos , Fenilglioxal/análogos & derivados , Bases de Schiff/química , Animais , Linhagem Celular Tumoral , Cristalografia por Raios X/métodos , Humanos , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Células NIH 3T3 , Fenilglioxal/química , Fenilglioxal/farmacologia , Bases de Schiff/farmacologia , Relação Estrutura-Atividade
8.
Amino Acids ; 52(3): 397-407, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31932980

RESUMO

Schiff bases represent a class of molecules widely studied for their importance in organic and coordination chemistry. Despite the large amount of studies on the chemical and biological properties of the Schiff bases, the different experimental conditions prevent a useful comparison to search for a correlation structure-activity. Moreover, literature is lacking in comprehensive data on the spectroscopic characterization of these compounds. For this reason, six Schiff bases, derived from salicylaldehyde and natural amino acids were fully characterized by nuclear magnetic resonance and infrared spectroscopy, and their aqueous solution equilibria, antiproliferative activity and DNA-binding activity were examined. All experimental conditions were kept constants to achieve comparable information and useful insights about their structure-activity correlation. The synthesized compounds showed DNA binding constants in the 101-102 M-1 range, depending on the substituent present in the amino acid side-chain, and resulted devoid of significant cytotoxic activity against the different human tumor cell lines showing IC50 values higher than 100 µM.


Assuntos
Aldeídos/química , Aminoácidos/síntese química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Bases de Schiff/síntese química , Bases de Schiff/farmacologia , Linhagem Celular Tumoral , Humanos , Hidrogenação , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Espectrofotometria Infravermelho
9.
Carbohydr Polym ; 230: 115671, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31887926

RESUMO

Cellulose-based materials are widely used in the biomedical field. However, the lack of antibacterial activities of cellulose fibers inevitably causes bacterial infection damages. In this study, Schiff base was first introduced to endow the cellulose fibers good antibacterial property and copper ions were complexed with Schiff base to form a complex. The prepared complex greatly enhanced the antibacterial properties of the cellulose fibers. FT-IR, XRD, UV-vis and SEM-EDS results proved the successful synthesis of Schiff base and its copper (II) complex. The antibacterial tests indicated that the width of the inhibition zone of the as-prepared cellulose-based Schiff base-Cu (II) complex against E. coli and S. aureus increased by 472 % and 823 %, respectively, in comparison to the Schiff base ligand. This significant increase could be attributed to the incorporation of the copper ions (II). This Schiff base-Cu (II) complex containing cellulose-based antibacterial materials are expected to be widely used for biomedical application.


Assuntos
Antibacterianos/farmacologia , Celulose/farmacologia , Complexos de Coordenação/farmacologia , Cobre/farmacologia , Bases de Schiff/farmacologia , Bandagens , Materiais Biocompatíveis/farmacologia , Celulose/química , Escherichia coli/efeitos dos fármacos , Bases de Schiff/química , Staphylococcus aureus/efeitos dos fármacos
10.
Spectrochim Acta A Mol Biomol Spectrosc ; 225: 117457, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31450223

RESUMO

Drug-binding and interactions with plasma proteins strongly affect their efficiency of delivery, hence considered as a key factor in determining the overall pharmacological action. Alpha-1-acid glycoprotein (AGP), a second most abundant plasma protein in blood circulation, has unique drug binding ability and involved in the transportation of various compounds. Here, we have investigated the mechanism of interaction between AGP and potential Cu/Zn metallo-drugs of benzimidazole derived organic motifs (CuL2 and ZnL2, where L is Schiff base ligand) by applying integrated spectroscopic, biophysical techniques and computational molecular docking analyses. We found that both the metallo-drugs (CuL2 and ZnL2) were bound at the central cavity of AGP interacting with the residues of lobe I, lobe II as well as lobe III. The binding of metallo-drugs to AGP occurs in 1:1 M ratios. Hydrogen bonding, electrostatic and hydrophobic interactions played a significant role in stabilizing the AGP-metallo-drug complexes. Binding affinities of both the metallo-drugs towards AGP at 298 K were of the order of 104-105 M-1, corresponding to Gibbs free energy of stabilization of approximately -5.50 to -6.62 kcal mol-1. Furthermore, the spectroscopic investigation by circular dichroism and synchronous fluorescence analyses suggest conformational changes in AGP upon the binding of metallic compounds.


Assuntos
Benzimidazóis/química , Compostos Organometálicos/química , Orosomucoide/química , Animais , Benzimidazóis/metabolismo , Benzimidazóis/farmacologia , Sítios de Ligação , Bovinos , Dicroísmo Circular , Cobre/química , Transferência Ressonante de Energia de Fluorescência , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Técnicas In Vitro , Ligantes , Simulação de Acoplamento Molecular , Compostos Organometálicos/metabolismo , Compostos Organometálicos/farmacologia , Orosomucoide/efeitos dos fármacos , Orosomucoide/metabolismo , Ligação Proteica , Conformação Proteica , Bases de Schiff/química , Bases de Schiff/metabolismo , Bases de Schiff/farmacologia , Espectrometria de Fluorescência , Eletricidade Estática , Zinco/química
11.
Int J Biol Macromol ; 146: 1100-1110, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31682857

RESUMO

A novel, eco-friendly aminated chitosan Schiff's base (ACSSB@ZnO) was developed and utilized to remove MO from aqueous environment. The impact of different significant parameters, for example, pH (3-11), adsorbent dose (0.1-0.6 g), contact time (0-120 min), and temperature (303-323 K) have been explored by batch process. Kinetic data was illustrated by pseudo-second-order model and the isotherms fitted well with Langmuir isotherm model. The highest sorption capacity of ACSSB@ZnO was observed to be 111.11 mg/g at 323 K. Positive enthalpy and entropy values demonstrated that the MO adsorption procedure was an endothermic. Negative Gibbs free energy values implied the spontaneous nature of the adsorption system. Moreover, reusability experiments were studied and it can be regenerated by using NaOH as effluent.


Assuntos
Compostos Azo/isolamento & purificação , Quitosana/síntese química , Corantes/isolamento & purificação , Bases de Schiff/síntese química , Bases de Schiff/farmacologia , Poluentes Químicos da Água/isolamento & purificação , Adsorção , Aminação , Animais , Quitosana/química , Humanos , Concentração de Íons de Hidrogênio , Cinética , Células MCF-7 , Masculino , Camundongos , Espectroscopia de Prótons por Ressonância Magnética , Bases de Schiff/química , Espectroscopia de Infravermelho com Transformada de Fourier , Propriedades de Superfície , Fatores de Tempo , Difração de Raios X , Óxido de Zinco/química
12.
Eur J Med Chem ; 185: 111780, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31655429

RESUMO

Two new series of pyrrolizine-5-carboxamides were synthesized and evaluated for their anticancer and anti-inflammatory activities. The new compounds exhibited potent cytotoxicity (IC50 = 0.10-22.96 µM) against three cancer (MCF-7, A2780 and HT29) cell lines with selectivity index in the range of 1-258. Moreover, these compounds also exhibited significant anti-inflammatory activity (18.13-44.51% inhibition of inflammation) mediated by inhibition of COX-1/2 with preferential inhibition of COX-2. The study of SAR revealed favorable cytotoxic outcomes of the aliphatic side chain and 4-thiazolidinone moiety at C6 of the pyrrolizine nucleus, while anti-inflammatory activities was improved with the (hetero)aromatic substituents. The IC50 values which inhibit COX-2 were higher than those needed to inhibit the growth of cancer cell lines. Mechanistic studies also revealed inhibition of multiple kinases by compounds 12, 19 and 22. Moreover, compounds 12, 14, 16 and 22 induced cell cycle arrest and apoptosis in MCF-7 cells. Docking studies revealed nice fitting of the new compounds into COX-1/2. Additionally, compounds 12, 19 and 22 also exhibited higher affinity for CDK2 than CAN508. To sum up, the above-mentioned data highlight these compounds as promising anti-inflammatory and anticancer agents.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Desenho de Fármacos , Edema/tratamento farmacológico , Pirrolidinas/farmacologia , Tiazolidinas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células HT29 , Humanos , Células MCF-7 , Masculino , Estrutura Molecular , Pirrolidinas/síntese química , Pirrolidinas/química , Ratos , Bases de Schiff/síntese química , Bases de Schiff/química , Bases de Schiff/farmacologia , Relação Estrutura-Atividade , Tiazolidinas/química
13.
Oxid Med Cell Longev ; 2019: 1607903, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31687075

RESUMO

Schiff bases (SBs) are chemical compounds displaying a significant pharmacological potential. They are able to modulate the activity of many enzymes involved in metabolism and are found among antibacterial, antifungal, anti-inflammatory, antioxidant, and antiproliferative drugs. A new thiazolyl-triazole SB was obtained and characterized by elemental and spectral analysis. The antibacterial and antifungal ability of the SB was evaluated against Gram-positive and Gram-negative bacteria and against three Candida strains. SB showed good antibacterial activity against L. monocytogenes and P. aeruginosa; it was two times more active than ciprofloxacin. Anti-Candida activity was twofold higher compared with that of fluconazole. The effect of the SB on cell viability was evaluated by colorimetric measurement on cell cultures exposed to various SB concentrations. The ability of the SB to modulate oxidative stress was assessed by measuring MDA, TNF-α, SOD1, COX2, and NOS2 levels in vitro, using human endothelial cell cultures exposed to a glucose-enriched medium. SB did not change the morphology of the cells. Experimental findings indicate that the newly synthetized Schiff base has antibacterial activity, especially on the Gram-negative P. aeruginosa, and antifungal activity. SB also showed antioxidant and anti-inflammatory activities.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Células Endoteliais da Veia Umbilical Humana/patologia , Estresse Oxidativo/efeitos dos fármacos , Bases de Schiff/farmacologia , Tiazóis/farmacologia , Antioxidantes/farmacologia , Bactérias/efeitos dos fármacos , Biomarcadores/metabolismo , Compostos de Bifenilo/química , Sobrevivência Celular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamação/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Malondialdeído/metabolismo , Testes de Sensibilidade Microbiana , Picratos/química , Bases de Schiff/química , Tiazóis/química , Fator de Necrose Tumoral alfa/metabolismo
14.
Dalton Trans ; 48(47): 17673-17682, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31763642

RESUMO

Four new Ce(iii) complexes 1-4 with tridentate NNO-donor Schiff base ligands have been designed and successfully synthesized. These complexes were characterized by elemental analysis, IR, and ESI-MS, with formulas of [Ce(HL1)2(NO3)3]·2CH3OH (1), [Ce(L2)2(NO3)]·3H2O (2), [Ce(HL3)(L3)(NO3)Br]·H2O (3) and [Ce(L4)2(NO3)]·3H2O (4), in which ligands HL1-HL4 are respectively N'-[(1E)-pyridin-2-ylmethylidene]pyrazine-2-carbohydrazide (HL1), 2-(1-(salicyloylhydrazono)ethyl)pyrazine (HL2), N'-[(1E)-pyridin-2-ylmethylidene]pyridine-2-carbohydrazide (HL3) and 2-(1-(salicyloylhydrazono)ethyl) pyridine (HL4). X-ray single crystal diffraction analysis indicates that complex 1 crystallizes in the monoclinic system with the space group C2/c and the structure of complex 1 consists of a monomeric Ce(iii) species with a Ce(iii) moiety bonded to two tridentate Schiff base ligands, three nitrates and solvents. These complexes effectively inhibit the enzyme activities of PTPs (SHP-1, SHP-2, TCPTP and PTP1B), among which complex 3 shows the most potent inhibition of SHP-2 with the lowest IC50 value of 0.61 µM and displays obvious selectivity towards SHP-2. Its inhibition potency against SHP-2 was approximately 17, 4, and 5 fold higher than that against SHP-1, TCPTP and PTP1B, respectively. Further study discloses that complex 3 inhibits SHP-2 in a competitive manner. Fluorescence measurements indicate that complex 3 tightly binds to SHP-2 with a molar ratio of 1 : 1 and a binding constant of 5.45 × 105 M-1. Western blot experiments show that complex 3 promotes the phosphorylation of the SHP-2 substrate by the combination of the inhibition of the activity and expression of SHP-2. Moreover, complex 3 decreases the survival rate of A549 cells to 35.12% at 100 µM and induces apoptosis with an apoptosis rate of 12.06% at 50 µM. All these results suggest that complex 3 is a potential bi-functional inhibitor of the activity and expression of tyrosine phosphatase SHP-2.


Assuntos
Antineoplásicos/farmacologia , Cério/farmacologia , Complexos de Coordenação/farmacologia , Inibidores Enzimáticos/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cério/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Bases de Schiff/síntese química , Bases de Schiff/química , Bases de Schiff/farmacologia , Relação Estrutura-Atividade
15.
Molecules ; 24(20)2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31640238

RESUMO

The current study was chiefly designed to examine the antiproliferative and antioxidant activities of some novel quinazolinone(thione) derivatives 6-14. The present work focused on two main points; firstly, comparing between quinazolinone and quinazolinthione derivatives. Whereas, antiproliferative (against two cell lines namely, HepG2 and MCF-7) and antioxidant (by two methods; ABTS and DPPH) activities of the investigated compounds, the best quinazolinthione derivatives were 6 and 14, which exhibited excellent potencies comparable to quinazolinone derivatives 5 and 9, respectively. Secondly, we compared the activity of four series of Schiff bases which included the quinazolinone moiety (11a-d). In addition, the antiproliferative and antioxidant activities of the compounds with various aryl aldehyde hydrazone derivatives (11a-d) analogs were studied. The compounds exhibited potency that increased with increasing electron donating group in p-position (OH > OMe > Cl) due to extended conjugated systems. Noteworthy, most of antiproliferative and antioxidant activities results for the tested compounds are consistent with the DFT calculations.


Assuntos
Antineoplásicos/síntese química , Antioxidantes/síntese química , Quinazolinonas/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Proliferação de Células/efeitos dos fármacos , Teoria da Densidade Funcional , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Hidrazonas/farmacologia , Células MCF-7 , Estrutura Molecular , Quinazolinonas/química , Quinazolinonas/farmacologia , Bases de Schiff/síntese química , Bases de Schiff/química , Bases de Schiff/farmacologia , Relação Estrutura-Atividade , Tionas/química
16.
Metallomics ; 11(11): 1847-1863, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31553341

RESUMO

To develop new anti-tumour Pt(ii) agents, we designed and synthesized five Pt(ii) complexes. These Pt(ii) complexes were modified benzene rings of 2-hydroxybenzylidene with a hydrocarbyl or halogen group. The five Pt(ii) complexes possessed remarkable cytotoxicity against tumour cells in vitro. In particular, we investigated chemotherapeutic mechanisms of the complexes against A549cisR cells. The Pt(ii) complexes could bind to and cleave DNA, while also inducing arrest of the cell cycle in S phase, leading to down-regulation of the levels of cyclin-dependent kinases and cyclin and up-regulation of the expression of p21. The selected complex, C3, changed the mitochondrial membrane potential and induced apoptosis. C3 also inhibited the expression of the c-myc gene and downstream proteins, thereby inhibiting telomerase activity.


Assuntos
Hidrazonas/síntese química , Hidrazonas/farmacologia , Platina/farmacologia , Bases de Schiff/síntese química , Bases de Schiff/farmacologia , Animais , Apoptose/efeitos dos fármacos , Bovinos , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Forma Celular/efeitos dos fármacos , Cristalografia por Raios X , DNA/metabolismo , Humanos , Concentração Inibidora 50 , Ligantes , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/patologia , Telomerase/antagonistas & inibidores , Telomerase/metabolismo
17.
Mater Sci Eng C Mater Biol Appl ; 105: 110119, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31546342

RESUMO

A series of CuII, CoII, ZnII and NiII, complexes of 34,74-dimethyl-12,15,52,55-tetrahydro-2,4,6,8-tetraaza-1,5(2,5)-difurana-3,7(1,2)-dibenzenacyclooctaphane based ligand have been synthesized by template methodology. Characterization of the synthesized complexes has been carried out with the help of various physicochemical and spectroscopic techniques like Infra-Red, ESI-MS, ESR, UV-visible, CHN (elemental analyses), molar conductance, magnetic moment and NMR. Antimicrobial efficacy of the newly designed macrocyclic complexes has performed by the assistance of agar well diffusion method. In-vitro hemolytic and DNA binding studies were also performed in order to analyze or interpret the mode and binding efficiencies as well as the % hemolysis exhibited by the complexes. DFT/TD-DFT studies were carried out in order to elucidate the better insight into the structural parameters. Energy minimization and quantum chemical parameters were calculated using Gaussian09W program.


Assuntos
Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacologia , Bases de Schiff/síntese química , Bases de Schiff/farmacologia , Animais , Anti-Infecciosos/química , DNA/metabolismo , Espectroscopia de Ressonância de Spin Eletrônica , Peixes , Hemólise/efeitos dos fármacos , Compostos Macrocíclicos/química , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Conformação Molecular , Bases de Schiff/química , Espectrofotometria Infravermelho
18.
Bratisl Lek Listy ; 120(9): 646-649, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31475547

RESUMO

BACKGROUND: It has been demonstrated that proteasome inhibitors might be potential anticancer drugs. The copper complexes can be used as specific proteasome inhibitors in tumor cells able to induce apoptosis by the ubiquitin-proteasome pathway. The goal of our study was to test the cytotoxic and proteasome inhibitory effects of five Schiff base Cu(II) complexes - [Cu2(sal-D,L-glu)2(isoquinoline)2] . 2C2H5OH (1), [Cu(sal-5-met-L-glu)(H2O)].H2O (2), [Cu(ethanol)2(imidazole)4][Cu2(sal-D,L-glu)2(imidazole)2] (3), [Cu(sal-D,L-glu)(2-methylimidazole)] (4) on human lung carcinoma cells A549, cervix carcinoma cells HeLa and glioblastoma cells U-118MG. MATERIAL AND METHODS: For the cytotoxic analysis we used MTT test and for monitoring the proteasome inhibition western blot analysis. RESULTS: We have observed different cytotoxic effects of tested complexes on human cancer cells depending on the ligand present in their structure. Cu(II) complexes 4 and 5 were the most effective against A549 cells; all complexes were cytotoxic against HeLa cells and the complex 4 was the most effective against U-118MG. Moreover, we have detected the inhibition of the proteasome activity in human cancer cells A549 by Cu(II) complexes 1, 2 and 4 at IC50 concentration. CONCLUSION: Results of our study suggest that isoquinoline- and imidazole-based copper complexes could be used as inhibitors of the proteasome system in cancer cells A549 (Tab. 1, Fig. 1, Ref. 26).


Assuntos
Cobre/farmacologia , Inibidores de Proteassoma/farmacologia , Bases de Schiff/farmacologia , Células A549 , Antineoplásicos/farmacologia , Apoptose , Complexos de Coordenação/farmacologia , Células HeLa , Humanos , Complexo de Endopeptidases do Proteassoma
19.
J Microbiol Biotechnol ; 29(8): 1221-1229, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31370112

RESUMO

Mycobacterium tuberculosis, a causative pathogen of tuberculosis (TB), still threatens human health worldwide. To find a novel drug to eradicate this pathogen, we tested taurine-5- bromosalicylaldehyde Schiff base (TBSSB) as an innovative anti-mycobacterial drug using Mycobacterium smegmatis as a surrogate model for M. tuberculosis. We investigated the antimicrobial activity of TBSSB against M. smegmatis by plotting growth curves, examined the effect of TBSSB on biofilm formation, observed morphological changes by scanning electron microscopy and transmission electron microscopy, and detected differentially expressed proteins using two-dimensional gel electrophoresis coupled with mass spectrometry. TBSSB inhibited mycobacterial growth and biofilm formation, altered cell ultrastructure and intracellular content, and inhibited cell division. Furthermore, M. smegmatis adapted itself to TBSSB inhibition by regulating the metabolic pathways and enzymatic activities of the identified proteins. NDMA-dependent methanol dehydrogenase, NAD(P)H nitroreductase, and amidohydrolase AmiB1 appear to be pivotal factors to regulate the M. smegmatis survival under TBSSB. Our dataset reinforced the idea that Schiff base-taurine compounds have the potential to be developed as novel anti-mycobacterial drugs.


Assuntos
Aldeídos/farmacologia , Antibacterianos/farmacologia , Mycobacterium smegmatis/efeitos dos fármacos , Proteômica , Bases de Schiff/farmacologia , Taurina/análogos & derivados , Proteínas de Bactérias/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Parede Celular/efeitos dos fármacos , Redes e Vias Metabólicas/efeitos dos fármacos , Mycobacterium smegmatis/crescimento & desenvolvimento , Mycobacterium smegmatis/ultraestrutura , Mycobacterium tuberculosis , Taurina/farmacologia
20.
Biol Trace Elem Res ; 192(2): 153-159, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31407215

RESUMO

Metal complexes for medical applications are the promising area of research and metallo-drugs have been developed and evaluated to enhance the efficiency of drugs and minimize their side effects. This study describes the synthesis of a Schiff base ligand (Z)-3-bromo-5-((p-tolylimino)methyl)phenol from the reaction of 5-bromosalicilaldehyde and p-toluidine, and its subsequent complexation with nickel. Characterization and cell viability studies were performed for both Schiff base ligand and its metal complex with 1H-NMR, FTIR, TG analysis, and UV-VIS spectrometry. With the aim of proving the Ni complex formation, quantitative analysis was done with flame atomic absorption spectrometry. The recovery result obtained for the formed complex was 103.9%. The cell viability of human thyroid gland undifferentiated carcinoma cells (8305C) treated with the Ni-ligand complex was determined as 12.7 ± 0.17%. It was observed that the nickel complex could be a significant anticancer agent as tested by the MTT assay method. Graphical Abstract .


Assuntos
Antineoplásicos/farmacologia , Níquel/farmacologia , Compostos Organometálicos/farmacologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Camundongos , Níquel/química , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Bases de Schiff/química , Bases de Schiff/farmacologia , Neoplasias da Glândula Tireoide/patologia
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