RESUMO
α-Glucosidase inhibitory activity of galbanic acid and its new amide derivatives 3a-n were investigated. Galbanic acid and compounds 3a-n showed excellent anti-α-glucosidase activity with IC50 values ranging from 0.3 ± 0.3 µM to 416.0 ± 0.2 µM in comparison to positive control acarbose with IC50 value of = 750.0 ± 5.6. In the kinetic study, the most potent compound 3h demonstrated a competitive mode of inhibition with Ki = 0.57 µM. The interaction of the most potent compound 3h with the α-glucosidase was further elaborated by in vitro Circular dichroism assessment and in silico molecular docking and Molecular dynamics studies. Compound 3h was also non-cytotoxic on human normal cells. In silico study on pharmacokinetics and toxicity profile of the most potent galbanic acid derivatives demonstrated that these compounds are valuable lead compounds for further study in order to achieve new anti-diabetic agents.
Assuntos
Amidas , Inibidores de Glicosídeo Hidrolases , Simulação de Acoplamento Molecular , alfa-Glucosidases , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/síntese química , alfa-Glucosidases/metabolismo , Humanos , Relação Estrutura-Atividade , Estrutura Molecular , Amidas/química , Amidas/farmacologia , Amidas/síntese química , Relação Dose-Resposta a Droga , Saccharomyces cerevisiae/enzimologiaRESUMO
ABTRACT In this paper, a new series of isatin-sulphonamide based derivatives were designed, synthesised and evaluated as caspase inhibitors. The compounds containing 1-(pyrrolidinyl)sulphonyl and 2-(phenoxymethyl)pyrrolidin-1-yl)sulphonyl substitution at C5 position of isatin core exhibited better results compared to unsubstituted derivatives. According to the results of caspase inhibitory activity, compound 20d showed moderate inhibitory activity against caspase-3 and -7 in vitro compared to Ac-DEVD-CHO (IC50 = 0.016 ± 0.002 µM). Among the studied compounds, some active inhibitors with IC50s in the range of 2.33-116.91 µM were identified. The activity of compound 20d was rationalised by the molecular modelling studies exhibiting the additional van der Waals interaction of N-phenylacetamide substitution along with efficacious T-shaped π-π and pi-cation interactions. The introduction of compound 20d with good caspase inhibitory activity will help researchers to find more potent agents.
Assuntos
Inibidores de Caspase/farmacologia , Isatina/farmacologia , Simulação de Acoplamento Molecular , Sulfonamidas/farmacologia , Caspase 3 , Caspase 7 , Inibidores de Caspase/síntese química , Inibidores de Caspase/química , Relação Dose-Resposta a Droga , Humanos , Isatina/química , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
Selective area epitaxial growth is an important technique, both for monolithic device integration as well as for defect reduction in heteroepitaxy of crystalline materials on foreign substrates. While surface engineering with masking materials or by surface structuring is an effective means for controlling the location of material growth, as well as for improving crystalline properties of epitaxial layers, the commonly involved integral substrate heating presents a limitation, e.g., due to constraints ofr the thermal budget applicable to existing device structures. As a solution, an epitaxial growth approach using a laser source only locally heating the selected growth area, in combination with metal-organic precursors to feed a pyrolithic chemical reaction (also known as metal-organic vapor phase epitaxy, MOVPE), is presented. Without masking or surface structuring, local epitaxial growth of III-V compound semiconductor layers on a 50-1500 µm length-scale, with high structural and optical quality, is demonstrated. We discuss general design rules for reactor chamber, laser heating, temperature measurement, sample manipulation, gas mixing, and distinguish laser-assisted local MOVPE from conventional planar growth for the important compound semiconductor GaAs. Surface de-oxidation prior to growth is mandatory to realize smooth island surfaces. Linear growth rates in the range 0.5-9 µm/h are demonstrated. With increasing island diameter, the probability for plastic deformation within the island increases, depending on reactor pressure. A step-flow mode on the island surface can be achieved by establishing a sufficiently small temperature gradient across the island.
RESUMO
Sodium valproate (VPA) has 16 known metabolites in humans. The 2-ene-VPA has anti-convulsant efficacy and 4-ene-VPA is reported to contribute in VPA hepatotoxicity. The formation of 4-ene-VPA is catalyzed by cytochrome P450 2C9 (CYP2C9). CYP2C9 allele mutation is closely related to the attenuation of the enzymatic activity and 4-ene-VPA production. In the present work, VPA, 2-ene-VPA, and 4-ene-VPA in serum of patients receiving VPA were determined and the correlation between CYP2C9 polymorphism and 4-ene-VPA concentration was examined. Blood samplings in 68 patients were performed at two time-points (peak and trough) and one sample blood obtained from 50 healthy volunteers for genotype evaluation. Patients were divided into three groups (22 cases of monotherapy, 19 cases of enzyme inducer therapy, and 27 cases of polytherapy). There was a significant reduction in concentration of VPA and 4-ene-VPA between peak and trough time. In peak concentration, there was a significant correlation between 2-ene-VPA and VPA in all groups. The concentration of 4-ene-VPA in the enzyme inducer and polytherapy group was significantly higher than that of the monotherapy group. The allele frequencies of CYP2C9*1, CYP2C9*2, and CYP2C9*3 were 88.97%, 8.09%, and 2.94% in the patient group and 91%, 6%, and 3% in the normal group, respectively. There was no significant difference in allele frequency in two groups. Mutated alleles didn't have any significant effect on 4-ene-VPA production. No patient showed toxic level of 4-ene-VPA or saturation of ß-oxidation pathway. In conclusion, the role of CYP2C9*2 and CYP2C9*3 in attenuation of 4-ene-VPA formation cannot be confirmed.
Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Doença Hepática Induzida por Substâncias e Drogas/genética , Inibidores Enzimáticos/metabolismo , Polimorfismo Genético , Ácido Valproico/metabolismo , Adolescente , Adulto , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Citocromo P-450 CYP2C9 , Inibidores Enzimáticos/toxicidade , Feminino , Frequência do Gene , Genótipo , Humanos , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Ácido Valproico/análogos & derivados , Ácido Valproico/toxicidade , Adulto JovemRESUMO
We present an experimental study on the near-field light-matter interaction by tip-enhanced Raman scattering (TERS) with polarized light in three different materials: germanium-doped gallium nitride (GaN), graphene, and carbon nanotubes. We investigate the dependence of the TERS signal on the incoming light polarization and on the sample carrier concentration, as well as the Raman selection rules in the near-field. We explain the experimental data with a tentative quantum mechanical interpretation, which takes into account the role of plasmon polaritons, and the associated evanescent field. The driving force for the breakdown of the classical Raman selection rules in TERS is caused by photon tunneling through the perturbation of the evanescent field, with the consequent polariton annihilation. Predictions based on this quantum mechanical approach are in good agreement with the experimental data, which are shown to be independent of incoming light polarization, leading to new Raman selection rules for TERS.
RESUMO
Spatially separated ZnO pillars, typically 300 nm in diameter and 2 microm in height, are fabricated via a template-directed approach that leads to long-range hexagonal order. The templates of Au nanodisk arrays are obtained by using metal membranes as a lithography mask. The growth of ZnO pillars is performed in a double-tube system through vapor diffusion-deposition. The growth mechanism of the pillars is studied in detail and is proposed to be a combination of vapor-liquid-solid and vapor-solid models. The piezoelectric and optical properties of single pillars are characterized using piezoresponse force microscopy and micro-photoluminescence spectroscopy, respectively. The pillars show strong excitonic emissions up to room temperature, which indicate a relatively low defect density and good crystalline quality. The obtained piezoelectric coefficient d(33) is (7.5+/-0.6) pm V(-1), which is to our knowledge the first reported value for a single nanopillar.
Assuntos
Cristalização/métodos , Eletroquímica/métodos , Ouro/química , Nanoestruturas/química , Nanoestruturas/ultraestrutura , Nanotecnologia/métodos , Óxido de Zinco/química , Substâncias Macromoleculares/química , Teste de Materiais , Membranas Artificiais , Conformação Molecular , Óptica e Fotônica , Tamanho da Partícula , Propriedades de SuperfícieRESUMO
BACKGROUND: Breast cancer is the most common type of female cancer. One class of hormonal therapy for breast cancer drugs -non steroidal aromatase inhibitors- are triazole analogues. In this work, some derivatives of these drugs was designed and synthesized. All synthesized compounds were evaluated for their cytotoxic activities on breast cancer cell lines (MDA-MB-231, T47D and MCF-7). METHODS: Our synthetic route for designed compounds started from 4-bromotolunitrile which was reacted with 1H-1,2,4-triazole to afford 4-(4-cyanobenzyl)-1,2,4-triazole. The reaction of later compound with aromatic aldehydes led to formation of the designed compounds. Eleven novel derivatives 1a-k were tested for their cytotoxic activities on three human breast cancer cell lines. RESULTS: Among the synthesized compound, 4-[2-(3-chlorophenyl)-1-(1H-1,2,4-triazol-1-yl)ethenyl]benzonitrile (1c) showed the highest activity against MCF-7 and MDA-MB-231 cell lines and 4-[2-(4-methoxyphenyl)-1-(1H-1,2,4-triazol-1-yl)ethenyl]benzonitrile (1 h) exhibited highest activity against T47D cell line. According to cytotoxic activities results, compound 4-[2-(4-dimethylamino)-1-(1H-1,2,4-triazol-1-yl)ethenyl]benzonitrile (1 k) showed comparative activity against T47D and MDA-MB-231 cell lines with compound (1 h) and our reference drug Etoposide. CONCLUSION: In the process of anti-cancer drug discovery, to find new potential anti-breast cancer agents, we designed and synthesized a novel series of letrozole analogs. Cytotoxicity evaluation revealed that compounds (1c) and (1 k) were the most potent compounds with comparative activity with Etoposide. The results revealed that π-π interactions are responsible for the enzyme inhibitions of compounds (1 c) and (1 k).
Assuntos
Antineoplásicos Hormonais/síntese química , Antineoplásicos Hormonais/farmacologia , Inibidores da Aromatase/síntese química , Inibidores da Aromatase/farmacologia , Neoplasias da Mama/patologia , Desenho Assistido por Computador , Desenho de Fármacos , Simulação de Acoplamento Molecular , Nitrilas/síntese química , Nitrilas/farmacologia , Triazóis/síntese química , Triazóis/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Concentração Inibidora 50 , Letrozol , Células MCF-7 , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Ultrathin AlN/GaN crystalline porous freestanding nanomembranes are fabricated on Si(111) by selective silicon etching, and self-assembled into various geometries such as tubes, spirals, and curved sheets. Nanopores with sizes from several to tens of nanometers are produced in nanomembranes of 20-35 nm nominal thickness, caused by the island growth of AlN on Si(111). No crystal-orientation dependence is observed while releasing the AlN/GaN nanomembranes from the Si substrate indicating that the driving stress mainly originates from the zipping effect among islands during growth. Competition between different relaxation mechanisms is experimentally revealed for different nanomembrane geometries and well-described by numerical calculations. The cathodoluminescence emission from GaN nanomembranes reveals a weak peak close to the GaN bandgap, which is dramatically enhanced by electron irradiation.