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1.
Sci Rep ; 14(1): 2443, 2024 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-38287098

RESUMEN

Hydrothermal alteration processes are connected to many mineral formations, particularly auriferous deposits. In this study, airborne gamma-ray spectrometry (GRS) data and the analysis of radioactive materials (eU, eTh, and K) are applied to search for regions with hydrothermal alteration activity. An example is presented from Wadi Al-Allaqi, South Eastern Desert, Egypt. GRS was used to analyse various radiometric data to address potential mineral deposit areas, to map regions potentially showing metallic ore mineralisation, and to point out new geological mineral resources. The Kd (potassium deviation), "F" parameter and Th-normalisation of the K and eU anomalies were calculated, and locating new exploratory targets in the study area that exhibit high F-parameter, Kd, and K/eTh values was recommended. Additionally, the research region has a few isolated enriched spots of (K). Therefore, GRS data was used to characterise and estimate potential metallic ores, nonmetallic deposits, and gold ore zones associated with the alteration zones. Results show that most of the known mineral deposits and gold occurrences in the area, according to the metallogenic map of Egypt, are located in zones with a ratio value of (0.25-0.30) (K%/(U or Th ppm)) maps which may suggest a moderate degree of alteration. Also, most mineral deposits and gold occurrences are found in intermediate altered zones, or K-enriched sites, with a Kd% of (0.2. The work represents an attempt to map hydrothermal alteration zones associated with mineral deposits in the Wadi Al-Allaqi area. Generally, natural radiation characteristics and attributes suggest criteria that can be used globally for regional mineral exploration.

2.
Arch Pharm (Weinheim) ; 356(11): e2300345, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37661355

RESUMEN

Disubstituted five-membered heterocycles (1,2,4-triazole and 1,3,4 oxadiazole) were synthesized and investigated as inhibitors for signal transducer and activator of transcription 3 (STAT3) enzyme of breast cancer. 3-(Benzylthio)-5-(4-chlorobenzyl)-4H-1,2,4-triazol-4-amine (12d) was found to be the most active among the synthesized compounds with a half-maximal inhibitory concentration (IC50 ) value of 1.5 µM on MCF7 cells and was found to show a great inhibitory effect on the STAT3 enzyme. Compounds 9a,b,d,e,f, 11, and 12a,b,f,e show IC50 values in the range of 3-12 µM for the MCF7 cell line. Molecular modeling was used to investigate the biological results of the synthesized compounds.


Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Estructura Molecular , Relación Estructura-Actividad , Neoplasias de la Mama/tratamiento farmacológico , Factor de Transcripción STAT3 , Oxadiazoles/farmacología , Simulación del Acoplamiento Molecular
3.
Appl Radiat Isot ; 190: 110511, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36308978

RESUMEN

It is well known that many mineral deposits are related to hydrothermal processes, especially auriferous deposits. In this research paper, we show how to distinguish areas that have experienced hydrothermal activity, by construing airborne gamma-ray spectrometry data, especially potassium. An indirect application of aerial gamma-ray spectrometry technique is used to detect possible minerals deposits. In this region, an airborne gamma ray survey (K, eU and eTh) was carried out, based on irregular K, "F" parameter -, and Th-normalized of the K and eU anomalies. This work exhibits the mapping of hydrothermal regions possibly showing gold mineralization and the pointing out of new geological portions for this sequence, establishing prospective criteria for regional mineral exploration. We can suggest a new exploratory target, the area that is located next to Jabal Al-Ardiya (white colour on ternary map), which is characterized by high values of F-parameter, KD%, and K/eTh. Besides, enriched areas are found scattered in the north-eastern side of the study area. As result, the airborne gamma ray spectromertic data, might be used for estimation of prospective Gold Ore zones associated with the potassium alteration."


Asunto(s)
Monitoreo de Radiación , Monitoreo de Radiación/métodos , Oro , Estudios Prospectivos , Minerales , Potasio
4.
Int J Mol Sci ; 22(22)2021 Nov 12.
Artículo en Inglés | MEDLINE | ID: mdl-34830153

RESUMEN

A series of 3-(6-substituted phenyl-[1,2,4]-triazolo[3,4-b]-[1,3,4]-thiadiazol-3-yl)-1H-indoles (5a-l) were designed, synthesized and evaluated for anti-apoptotic Bcl-2-inhibitory activity. Synthesis of the target compounds was readily accomplished through a reaction of acyl hydrazide (1) with carbon disulfide in the presence of alcoholic potassium hydroxide to afford the corresponding intermediate potassium thiocarbamate salt (2), which underwent cyclization reaction in the presence of excess hydrazine hydrate to the corresponding triazole thiol (3). Further cyclisation reaction with substituted benzoyl chloride derivatives in the presence of phosphorous oxychloride afforded the final 6-phenyl-indol-3-yl [1,2,4]-triazolo[3,4-b]-[1,3,4]-thiadiazole compounds (5a-l). The novel series showed selective sub-micromolar IC50 growth-inhibitory activity against Bcl-2-expressing human cancer cell lines. The most potent 6-(2,4-dimethoxyphenyl) substituted analogue (5k) showed selective IC50 values of 0.31-0.7 µM against Bcl-2-expressing cell lines without inhibiting the Bcl-2-negative cell line (Jurkat). ELISA binding affinity assay (interruption of Bcl-2-Bim interaction) showed potent binding affinity for (5k) with an IC50 value of 0.32 µM. Moreover, it fulfils drug likeness criteria as a promising drug candidate.


Asunto(s)
Antineoplásicos/química , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Tiadiazoles/química , Triazoles/química , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Diseño de Fármacos , Células HeLa , Humanos , Concentración 50 Inhibidora , Células Jurkat , Modelos Químicos , Estructura Molecular , Terapia Molecular Dirigida/métodos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Relación Estructura-Actividad
5.
Arch Pharm (Weinheim) ; 354(12): e2100281, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34585758

RESUMEN

Globally, lung cancer and tuberculosis are considered to be very serious and complex diseases. Evidence suggests that chronic infection with tuberculosis (TB) can often lead to lung tumors; therefore, developing drugs that target both diseases is of great clinical significance. In our study, we designed and synthesized a suite of 14 new quinazolinones (5a-n) and performed biological investigations of these compounds in Mycobacterium tuberculosis (MTB) and cancer cell lines. In addition, we conducted a molecular modeling study to determine the mechanism of action of these compounds at the molecular level. Compounds that showed anticancer activity in the preliminary screening were further evaluated in three cancer cell lines (A549, Calu-3, and BT-474 cells) and characterized in an epidermal growth factor receptor (EGFR) binding assay. Cytotoxicity in noncancerous lung fibroblast cells was also evaluated to obtain safety data. Our theoretical and experimental studies indicated that our compounds showed a mechanism of action similar to that of erlotinib by inhibiting the EGFR tyrosine kinase. In turn, the antituberculosis activity of these compounds would be produced by the inhibition of enoyl-ACP-reductase. From our findings, we were able to identify two potential lead compounds (5i and 5l) with dual activity and elevated safety toward noncancerous lung fibroblast cells. In addition, our data identified three compounds with excellent anti-TB activities (compounds 5i, 5l, and 5n).


Asunto(s)
Antineoplásicos/farmacología , Antituberculosos/farmacología , Hidrazonas/farmacología , Quinazolinas/farmacología , Células A549 , Antineoplásicos/síntesis química , Antineoplásicos/química , Antituberculosos/síntesis química , Antituberculosos/química , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Línea Celular Tumoral , Receptores ErbB/antagonistas & inhibidores , Clorhidrato de Erlotinib/farmacología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Humanos , Hidrazonas/síntesis química , Hidrazonas/química , Neoplasias Pulmonares , Modelos Moleculares , Mycobacterium tuberculosis/efectos de los fármacos , Quinazolinas/síntesis química , Quinazolinas/química , Relación Estructura-Actividad , Tuberculosis/tratamiento farmacológico
6.
Bioorg Chem ; 115: 105264, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34416509

RESUMEN

The discovery of more selective and safer voltage-gated potassium channel blockers is an extremely demanding approach. Designing selective Kv1.5 inhibitors is very challenging as only limited data is available on this target due to a lacking crystal structure for this ion channel receptor. Herein, we synthesized a series of 21 novel quinazolinone dimers 3a-i, 5a-i and 10a-c. We tried to avoid structural features responsible for non-selectivity and for most potassium channel blockers' side effects in our design. In contrast to other works, which lack investigation over wide ranges of potassium and sodium channels, we screened the inhibitory activity of our synthesized compounds over multiple voltage-gated potassium channels, including six different human Kv1 channel subtypes Kv1.1, Kv1.2, Kv1.3, Kv1.4, Kv1.5 and Kv1.6 channels as well as Kv2.1, Kv3.1, Kv4.3, Kv7.2, Kv7.3, Kv10.1, hERG, and Shaker IR. Moreover, these compounds' selectivity was investigated on sodium channels Nav1.2, Nav1.4 and Nav1.5 and calcium channels Cav3.1-Cav3.3. The results revealed two compounds (3a and 3e) with low micromolar Kv1.5 inhibition activity with EC50 values of 5.1 ± 0.9 µM and 12.5 ± 1.1 µM, respectively. However, at higher concentrations, they also showed inhibitory activity on Kv1.3 and Kv1.1 channels. This might be due to structural similarities between these three Kv1 channel isoforms. Compound 3a shows a slight preference for Kv1.5. Interestingly, they lack any activity on other potassium channels (including hERG), sodium channels, and calcium channels. Our findings recommend quinazolinone dimers with ethylene linker as a potential new class of safer Kv1 inhibitors and a good start for designing more selective and potent Kv1.5 inhibitors.


Asunto(s)
Canales de Potasio con Entrada de Voltaje/antagonistas & inhibidores , Quinazolinonas/farmacología , Canales de Sodio Activados por Voltaje/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Canales de Potasio con Entrada de Voltaje/metabolismo , Quinazolinonas/síntesis química , Quinazolinonas/química , Relación Estructura-Actividad
7.
Int J Biol Macromol ; 184: 558-565, 2021 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-34174299

RESUMEN

Four novel chitosan hydrogels were successfully synthesized through the cross-linking reaction of chitosan with different concentrations of ethyl 5-(3,5-dihydroxy-1,4-dioxan-2-yl)-2-methylfuran-3-carboxylate. Their structures were confirmed by Fourier transform infrared spectroscopy (FT-IR), 13C Cross polarization magic angle spinning nuclear magnetic resonance spectroscopy (CP/MAS 13C NMR), ultraviolet-visible spectroscopy, thermogravimetric analysis (TGA, DTA), and X-ray diffraction (XRD). Cytotoxicity on hepatocellular carcinoma (HepG-2) cell line and a normal African green monkey kidney (Vero) cell line were studied using the MTT assay. The resultant hydrogels showed a good inhibitory effect comparing to the un-modified parent; the hydrogels with the lowest degree cross-linking (0.125 and 0.25 mol cross-linker per one chitosan residue) showed potent anticancer activity in the HepG2 cells with IC50 of 57.9 and 80.9 µg/ml, respectively. These results show that the newly synthesized cross-linked chitosan derivatives demonstrated more selectivity to the HepG2 than the Vero cells, indicating its potential for Investigation in the cure of hepatocellular carcinoma.


Asunto(s)
Antineoplásicos/síntesis química , Ácidos Carboxílicos/química , Quitosano/síntesis química , Bases de Schiff/química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Quitosano/química , Quitosano/farmacología , Chlorocebus aethiops , Células Hep G2 , Humanos , Hidrogeles/química , Espectroscopía Infrarroja por Transformada de Fourier , Células Vero , Difracción de Rayos X
8.
Environ Sci Pollut Res Int ; 28(16): 19664-19676, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33405141

RESUMEN

Brown seaweeds are rich in polysaccharides, such as fucoidan (FUC) which has shown beneficial effects in several medical conditions. The aim of the present study was to assess the antioxidant, anti-inflammatory, and hepatoprotective properties of Colpomenia sinuosa- and Sargassum prismaticum-isolated FUC in vitro and in vivo. The hot acid extraction method was used to isolate FUC from C. sinuosa (FCS) and S. prismaticum (FSP) species. The antioxidant, anticancer, as well as the effect on neurotransmitter-degrading enzyme and disaccharidase activities were measured using standard protocols. Moreover, the hepatoprotective effect of two FCS doses (100 and 200 mg/kg) on paracetamol-administered rats (one dose of 1 g/kg) were evaluated by measuring blood liver function markers, hepatic pro-oxidants as malondialdehyde (MDA) and nitric oxide (NO), antioxidants as glutathione (GSH) and glutathione peroxidase (GPx), proinflammatory markers as inducible nitric oxide synthase (iNOS), interleukin 1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and liver histology. The crude fucoidan yield was 15.6% and 14.8% of C. sinuosa and S. prismaticum dry weights, respectively. The antioxidant effects and cytotoxic activity on hepatic cancer cell were higher for FCS than FSP. Moreover, in vivo data showed that FCS administration at both doses significantly improved liver functions and alleviated histological alterations, hepatic inflammation, and oxidative stress following paracetamol intake. In conclusion, fucoidan exerts anti-inflammatory, antidigestive enzyme activity, antioxidant, anticancer, and hepatoprotective effects.


Asunto(s)
Phaeophyceae , Polisacáridos , Animales , Antioxidantes/metabolismo , Hígado/metabolismo , Estrés Oxidativo , Polisacáridos/metabolismo , Polisacáridos/farmacología , Ratas
9.
Int J Mol Sci ; 21(23)2020 Nov 26.
Artículo en Inglés | MEDLINE | ID: mdl-33256166

RESUMEN

A series of 2-(1H-indol-3-yl)-5-substituted-1,3,4-oxadiazoles, 4a-m, were designed, synthesized and tested in vitro as potential pro-apoptotic Bcl-2 inhibitory anticancer agents based on our previously reported hit compounds. Synthesis of the target 1,3,4-oxadiazoles was readily accomplished through a cyclization reaction of indole carboxylic acid hydrazide 2 with substituted carboxylic acid derivatives 3a-m in the presence of phosphorus oxychloride. New compounds 4a-m showed a range of IC50 values concentrated in the low micromolar range selectively in Bcl-2 positive human cancer cell lines. The most potent candidate 4-trifluoromethyl substituted analogue 4j showed selective IC50 values of 0.52-0.88 µM against Bcl-2 expressing cell lines with no inhibitory effects in the Bcl-2 negative cell line. Moreover, 4j showed binding that was two-fold more potent than the positive control gossypol in the Bcl-2 ELISA binding affinity assay. Molecular modeling studies helped to further rationalize anti-apoptotic Bcl-2 binding and identified compound 4j as a candidate with drug-like properties for further investigation as a selective Bcl-2 inhibitory anticancer agent.


Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Diseño de Fármacos , Oxadiazoles/síntesis química , Oxadiazoles/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Antineoplásicos/química , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Oxadiazoles/química , Unión Proteica/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo
10.
Materials (Basel) ; 13(19)2020 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-33023271

RESUMEN

Vanadium carbide is known, for its hardness and other unique properties, as a refractory material. The synthesis of vanadium carbide is always associated with the utilization of expensive active metals, such as aluminum, calcium and magnesium, as a reducing agent to extract the vanadium metal from its corresponding oxide, followed by carbidization. The carbidization of reduced vanadium requires a complicated process and elevated temperature. Mechanical activation to synthesize vanadium carbide from its corresponding oxide and carbon source represents a promising, straightforward and less energy-intensive route. In the present study, vanadium carbide is synthesized by the carbothermic reduction of a mechanically activated mixture of V2O5 and carbon black as reducing agents without any additives. The reduction process is monitored by means of thermogravimetric analysis. The reduction products are characterized by X-ray diffraction and field emission scanning electron microscope. It is found that V8C7 with an average crystallite size of 88 nm can be synthesized from a V2O5-C mixture after milling for 15 h and further heating at 1050 °C for 1 h in an inert atmosphere.

11.
Int J Biol Macromol ; 163: 2180-2188, 2020 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-32946942

RESUMEN

Two novel chitosan Schiff bases namely chitosan pyrazolo[3,4-b]quinoxaline Schiff base (Ch-PQ1) and chitosan phenyl-1H-pyrazolo[3,4-b]quinoxaline Schiff base (Ch-PQ2) were synthesized as a modification of chitosan in order to increase its ability in heavy metal removal from wastewater. Their structures were characterized by FT-IR spectroscopy, TGA analysis and X-ray diffraction. They were tested for the removal of hexavalent chromium from synthetic samples. In addition pH conditions, polymer dosage, Cr (VI) initial concentration and contact time were studied as a key factor for the adsorption process. Kinetic studies of the removal process were also clarified. Furthermore, experimental equilibrium data were fitted to Langmuir and Freundlich adsorption isotherms. Both chitosan Schiff bases showed high removal efficiency, the result indicated that Cr (VI) removal using Ch-PQ1 and Ch-PQ2 was 96.4% and 98.8% respectively.


Asunto(s)
Quitosano/química , Cromo/aislamiento & purificación , Aguas Residuales/química , Contaminantes Químicos del Agua/aislamiento & purificación , Quitosano/síntesis química , Quitosano/farmacología , Cromo/toxicidad , Bases de Schiff/síntesis química , Bases de Schiff/química , Bases de Schiff/farmacología , Espectroscopía Infrarroja por Transformada de Fourier , Contaminantes Químicos del Agua/toxicidad , Purificación del Agua/métodos
12.
Int J Biol Macromol ; 158: 1102-1109, 2020 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-32376248

RESUMEN

Chitosan/aroylhydrazine composite were synthesized in hydrogel form in which aroylhyrazines, heteroaroylhydrazines as well as p-tolylsulphonylhydrazine embedded in the cross linked Chitosan/oxalic acid network. Their structures were characterized by (elemental analysis, FT-IR, 1H NMR, and XRD). Antimicrobial behavior and Cytotoxicity screening of the examined compounds against breast, colon and hepatocellular cancer were investigated. The obtained data revealed that the examined compounds have promising cell growth inhibitory effect on the cell lines as compared to standard. Also, some of the newly synthesized derivatives had shown better antibacterial and antifungal activities, comparing with that of the parent chitosan.

13.
Egypt J Chem ; 61(Conference Iss): 9-25, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-31937997

RESUMEN

AS THE RESISTANCE of Staphylococcus aureus to antibiotics represents a major threat to global health, anti-infectives with novel mechanisms must be developed. Novel compounds were generated as potential phenylalanine tRNA synthetase (PheRS) inhibitors based on the published homology model of S. aureus PheRS to aid the design process using Molecular Operating Environment (MOE) software. PheRS was selected as it is structurally unique enzyme among the aminoacyl-tRNA synthetases (aaRS), it is considerably different from human cytosolic and human mitochondrial aaRS and it is essential and conserved across bacterial species. The designed compounds were synthesized according to different clear schemes. The compounds were confirmed by 1H NMR, 13C NMR, HRMS and/or microanalysis, and they were microbiologically evaluated.

14.
J Mol Graph Model ; 73: 36-47, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-28235746

RESUMEN

Increased resistance of MRSA (multidrug resistance Staphylococcus aureus) to anti-infective drugs is a threat to global health necessitating the development of anti-infectives with novel mechanisms of action. Phenylalanine tRNA synthetase (PheRS) is a unique enzyme of the aminoacyl-tRNA synthetases (aaRSs), which are essential enzymes for protein biosynthesis. PheRS is an (αb)2 tetrameric enzyme composed of two alpha subunits (PheS) and two larger beta subunits (PheT). Our potential target in the drug development for the treatment of MRSA infections is the phenylalanine tRNA synthetase alpha subunit that contains the binding site for the natural substrate. There is no crystal structure available for S. aureus PheRS, therefore comparative structure modeling is required to establish a putative 3D structure for the required enzyme enabling development of new inhibitors with greater selectivity. The S. aureus PheRS alpha subunit homology model was constructed using Molecular Operating Environment (MOE) software. Staphylococcus haemolyticus PheRS was the main template while Thermus thermophilus PheRS was utilised to predict the enzyme binding with tRNAphe. The model has been evaluated and compared with the main template through Ramachandran plots, Verify 3D and Protein Statistical Analysis (ProSA). The query protein active site was predicted from its sequence using a conservation analysis tool. Docking suitable ligands using MOE into the constructed model were used to assess the predicted active sites. The docked ligands involved the PheRS natural substrate (phenylalanine), phenylalanyl-adenylate and several described S. aureus PheRS inhibitors.


Asunto(s)
Fenilalanina-ARNt Ligasa/química , Staphylococcus aureus/enzimología , Homología Estructural de Proteína , Secuencia de Aminoácidos , Anticodón/genética , Sitios de Unión , Metales/metabolismo , Simulación del Acoplamiento Molecular , Conformación de Ácido Nucleico , Filogenia , Subunidades de Proteína/metabolismo , ARN de Transferencia de Fenilalanina/química , ARN de Transferencia de Fenilalanina/metabolismo , Alineación de Secuencia , Thermus thermophilus/enzimología
15.
Phys Chem Chem Phys ; 19(9): 6688-6697, 2017 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-28210718

RESUMEN

A hydrophilic tris(tetrachlorotriaryl)methyl (tetrachloro-TAM) radical labelled 50% with 13C at the central carbon atom was prepared. The mixture of isotopologue radicals was characterised by continuous wave and pulsed X-band electron paramagnetic spectroscopy (EPS). For the pharmaceutical and medical applications planned, the quantitative influence of oxygen, viscosity, temperature and pH on EPR line widths was studied in aqueous buffer, DMSO, water-methanol and water-glycerol mixtures. Under in vivo conditions, pH can be disregarded. There is a clear oxygen dependence of the width of the 12C isotopologue single EPR line in aqueous solutions while changes in rotational motion (viscosity) are observable only in the doublet lines of the central carbon of the 13C isotopologue. The tetrachloro-TAM proved to be very stable as a solid. Its thermal decay was determined quantitatively by thermal annealing. Towards ascorbic acid as a reducing agent and towards an oocyte cell extract it had a half-life of approx. 60 and 10 min. Thus for in vivo applications, 50% 13C tetrachloro-TAMs are suitable for selective and simultaneous oxygen and macroviscosity measurements in a formulation, e.g. nanocapsules.

16.
Bioorg Med Chem Lett ; 27(4): 1037-1040, 2017 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-28087272

RESUMEN

A series of 5-(1H-indol-3-yl)-N-aryl-1,3,4-oxadiazol-2-amines 8a-j has been designed, synthesized and tested in vitro as potential pro-apoptotic Bcl-2-inhibitory anticancer agents based on our previous lead compound 8a. Synthesis of the target compounds was readily accomplished through a cyclisation reaction between indole-3-carboxylic acid hydrazide (5) and substituted isothiocyanates 6a-j, followed by oxidative cyclodesulfurization of the corresponding thiosemicarbazide 7a-j using 1,3-dibromo-5,5-dimethylhydantoin. Active compounds of the series 8a-j were found to have sub-micromolar IC50 values selectively in Bcl-2 expressing human cancer cell lines; notably the 2-nitrophenyl analogue 8a was found to exhibit potent activity, and compounds 8a and 8e possessed comparable Bcl-2 binding affinity (ELISA assay) to the established natural product-based Bcl-2 inhibitor, gossypol. Molecular modeling studies helped to further rationalise anti-apoptotic Bcl-2 binding, and identified compounds 8a and 8e as candidates for further development as Bcl-2 inhibitory anticancer agents.


Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Oxadiazoles/síntesis química , Oxadiazoles/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos
17.
Molecules ; 21(6)2016 May 25.
Artículo en Inglés | MEDLINE | ID: mdl-27231891

RESUMEN

Chitosan was reacted with four concentrations (2.5, 5, 10 and 20 mmol) of glutamic acid resulting in four types of glutamic-chitosan hydrogels (GCs), the activity of the resulted compounds on the removal of copper(II) and nickel(II) from wastewater were tested. The results indicated that by increasing glutamic acid concentration from GCs-1 to GCs-4, the efficiency of removing Cu(II) and Ni(II) were decreased, which may be due to a decrease in the pore size of the hydrogels as a result of the increased degree of crosslinking.


Asunto(s)
Hidrogeles/química , Aguas Residuales/química , Contaminantes Químicos del Agua/química , Purificación del Agua , Quitosano/química , Cobre/química , Humanos , Níquel/química
18.
J Org Chem ; 80(13): 6754-66, 2015 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-26020133

RESUMEN

Tissue oxygenation plays an important role in the pathophysiology of various diseases and is often a marker of prognosis and therapeutic response. EPR (ESR) is a suitable noninvasive oximetry technique. However, to reliably deploy soluble EPR probes as oxygen sensors in complex biological systems, there is still a need to investigate and improve their specificity, sensitivity, and stability. We reproducibly synthesized various derivatives of tetrathiatriarylmethyl and tetrachlorotriarylmethyl (trityl) radicals. Hydrophilic radicals were investigated in aqueous solution mimicking physiological conditions by, e.g., variation of viscosity and ionic strength. Their specificity was satisfactory, but the oxygen sensitivity was low. To enhance the capability of trityl radicals as oxygen sensors, encapsulation into oily core nanocapsules was performed. Thus, different lipophilic triesters were prepared and characterized in oily solution employing oils typically used in drug formulations, i.e., middle-chain triglycerides and isopropyl myristate. Our screening identified the deuterated ethyl ester of D-TAM (radical 13) to be suitable. It had an extremely narrow single EPR line under anoxic conditions and excellent oxygen sensitivity. After encapsulation, it retained its oxygen responsiveness and was protected against reduction by ascorbic acid. These biocompatible and highly sensitive nanosensors offer great potential for future EPR oximetry applications in preclinical research.


Asunto(s)
Radicales Libres/química , Oxígeno/química , Compuestos de Tritilo/síntesis química , Espectroscopía de Resonancia por Spin del Electrón/métodos , Interacciones Hidrofóbicas e Hidrofílicas , Estructura Molecular , Oximetría , Compuestos de Tritilo/química
19.
Biomed Chromatogr ; 29(7): 998-1007, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25417559

RESUMEN

The prerequisites for forensic confirmatory analysis by LC/MS/MS with respect to European Union guidelines are chromatographic separation, a minimum number of two MS/MS transitions to obtain the required identification points and predefined thresholds for the variability of the relative intensities of the MS/MS transitions (MRM transitions) in samples and reference standards. In the present study, a fast, sensitive and robust method to quantify tramadol, chlorpheniramine, dextromethorphan and their major metabolites, O-desmethyltramadol, dsmethyl-chlorpheniramine and dextrophan, respectively, in human plasma using ibuprofen as internal standard (IS) is described. The analytes and the IS were extracted from plasma by a liquid-liquid extraction method using ethyl acetate-diethyl-ether (1:1). Extracted samples were analyzed by ultra-high-performance liquid chromatography coupled to electrospray ionization tandem mass spectrometry (UHPLC-ESI-MS/MS). Chromatographic separation was performed by pumping the mobile phase containing acetonitrile, water and formic acid (89.2:11.7:0.1) for 2.0 min at a flow rate of 0.25 µL/min into a Hypersil-Gold C18 column, 20 × 2.0 mm (1.9 µm) from Thermoscientific, New York, USA. The calibration curve was linear for the six analytes. The intraday precision (RSD) and accuracy (RE) of the method were 3-9.8 and -1.7-4.5%, respectively. The analytical procedure herein described was used to assess the pharmacokinetics of the analytes in 24 healthy volunteers after a single oral dose containing 50 mg of tramadol hydrochloride, 3 mg chlorpheniramine maleate and 15 mg of dextromethorphan hydrobromide.


Asunto(s)
Clorfeniramina/sangre , Cromatografía Líquida de Alta Presión/métodos , Dextrometorfano/sangre , Espectrometría de Masas en Tándem/métodos , Tramadol/sangre , Clorfeniramina/química , Clorfeniramina/farmacocinética , Dextrometorfano/química , Dextrometorfano/farmacocinética , Estabilidad de Medicamentos , Humanos , Límite de Detección , Modelos Lineales , Reproducibilidad de los Resultados , Tramadol/química , Tramadol/farmacocinética
20.
Iran J Pharm Res ; 13(3): 893-8, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25276189

RESUMEN

Selenium plays an important role in biological system due to its incorporation in glutathione peroxidases and thioredoxin reductase as prosthetic group, the pharmacological studies of synthetic organoseleno-compounds revealed these molecules to be used as antioxidants, enzyme inhibitors, neuroprotectors, antitumor, anti-infectious agents, cytokine inducers and immuno-modulators. The present study was undertaken to elucidate Synthesis and biological effect Di (p-methylbenzoyl) diselenide (DMBDS) in-vitro. Di (p-methylbenzoyl) diselenide DMBDS was synthesized and its structure was confirmed by different spectroscopy techniques. In-vitro dose response of DMBDS on lipid peroxidation, nitrite content, GPx and arginase activities beside blood coagulation were measured. Acute toxicological effects were assessed by single orally injected Swiss albino mice with different DMBDS concentrations. In-vitro results revealed that DMBDS induces oxidative stress, elevation of arginase activity and acts as coagulant.

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