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1.
Chem Pharm Bull (Tokyo) ; 72(1): 121-126, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38296514

RESUMEN

In clinical diagnosis, fluorescent particles are applied to detect analytes in biofluids, such as blood and saliva. However, current fluorescence detection methods have not been optimized to account for the overlapping autofluorescence peaks of biological substances. Gold and silver nanoclusters are known to the novel fluorescent materials and their emission wavelengths depend on cluster size. In this study, we developed fluorescent silica nanoparticles using gold-silver alloy nanoclusters and chitosan (CS) (NH2-SiO2@Au@CS@AuAg) by the layer-by-layer method. Under UV-light irradiation at 365 nm, the emission wavelength of NH2-SiO2@Au@CS@AuAg reached 750 nm in the near-IR region. Scanning electron microscopy images revealed that the shape of NH2-SiO2@Au@CS@AuAg was uniform and spherical. The fluorescence spectrum of horse blood obtained in the presence of NH2-SiO2@Au@CS@AuAg contained a specific fluorescence peak attributed to NH2-SiO2@Au@CS@AuAg, which was distinguishable from the autofluorescence peaks. These results showed that NH2-SiO2@Au@CS@AuAg has advantageous fluorescence properties for clinical diagnostic applications.


Asunto(s)
Aleaciones de Oro , Nanopartículas del Metal , Animales , Caballos , Plata , Dióxido de Silicio , Oro
2.
Chem Pharm Bull (Tokyo) ; 72(3): 340-344, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38538315

RESUMEN

In clinical diagnosis, magnetic polystyrene nanoparticles (MPS NPs) are commonly applied to, e.g., the chemiluminescent immunoassay (CLEIA). However, the conventional preparation method of MPS NPs requires a long duration of heating to form polymer particles, which is inefficient. In this study, we prepared MPS NPs by emulsion solvent-evaporation without heating. We evaluated the effect of the solvent in the water and organic phases on the magnetic particle content. MPS NPs prepared by 4% (v/v) MeOH aqueous solution and adding stearic acid (SA) (4MeSA-MPS NPs) exhibited the highest magnetic particle content. Furthermore, CLEIA analysis indicates that the C-reactive protein detection limit is 80 pg/mL. Thus, 4MeSA-MPS NPs are promising for clinical diagnoses.


Asunto(s)
Inmunoensayo , Nanopartículas , Poliestirenos , Emulsiones , Inmunoensayo/métodos , Fenómenos Magnéticos , Tamaño de la Partícula , Solventes , Agua , Luminiscencia
3.
Bioorg Med Chem ; 59: 116657, 2022 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-35219181

RESUMEN

Fibroblast growth factor receptor 3 (FGFR3) is an attractive therapeutic target for the treatment of bladder cancer patients harboring genetic alterations in FGFR3. We identified pyrimidine derivative ASP5878 (27) with improved metabolic stability and suppressed human ether-á-go-go related gene (hERG) channel inhibitory activity by the optimization of lead compound 1. Based on prediction of the metabolites of 1, an ether linker was introduced in place of the ethylene linker to improve metabolic stability. Moreover, conversion of the phenyl moiety into the pyrazole ring resulted in the suppression of hERG channel inhibitory activity, possibly due to the weaker π-π stacking interaction with Phe656 in the hERG channel by a reduction in π-electrical density of the aromatic ring. ASP5878 showed potent in vitro FGFR3 enzyme and cell growth inhibitory activity, and in vivo FGFR3 autophosphorylation inhibitory activity. Moreover, ASP5878 did not affect the hERG current up to 10 µM by in vitro patch-clamp assay, and a single oral dose of ASP5878 at 1, 10, and 100 mg/kg did not induce serious adverse effects on the central nervous, cardiovascular, and respiratory systems in dogs. Furthermore, ASP5878 exhibited lower total clearance than hepatic blood flow and high oral bioavailability in rats and dogs, and moderate brain penetration in rats.


Asunto(s)
Pirazoles , Pirimidinas , Animales , Perros , Canal de Potasio ERG1/metabolismo , Canales de Potasio Éter-A-Go-Go , Éteres , Humanos , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Pirimidinas/farmacología , Ratas , Relación Estructura-Actividad
4.
Bioorg Med Chem ; 33: 116019, 2021 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-33486159

RESUMEN

Fibroblast growth factor receptor 3 (FGFR3) is an attractive therapeutic target for the treatment of patients with bladder cancer harboring genetic alterations in FGFR3. We identified pyrimidine derivative 20b, which induced tumor regression following oral administration to a bladder cancer xenograft mouse model. Compound 20b was discovered by optimizing lead compound 1, which we reported previously. Specifically, reducing the molecular size of the substituent at the 4-position and replacing the linker of the 5-position in the pyrimidine scaffold resulted in an increase in systemic exposure. Furthermore, introduction of two fluorine atoms into the 3,5-dimethoxyphenyl ring enhanced FGFR3 inhibitory activity. Molecular dynamics (MD) simulation of 20b suggested that the fluorine atom interacts with the main chain NH moiety of Asp635 via a hydrogen bond.


Asunto(s)
Antineoplásicos/farmacología , Pirimidinas/farmacología , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Simulación de Dinámica Molecular , Estructura Molecular , Células 3T3 NIH , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Pirimidinas/administración & dosificación , Pirimidinas/química , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/metabolismo , Solubilidad , Relación Estructura-Actividad , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/patología
5.
Bioorg Med Chem ; 28(10): 115453, 2020 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-32278710

RESUMEN

Fibroblast growth factor receptor 3 (FGFR3) is an attractive therapeutic target for the treatment of bladder cancer. We identified 1,3,5-triazine derivative 18b and pyrimidine derivative 40a as novel structures with potent and highly selective FGFR3 inhibitory activity over vascular endothelial growth factor receptor 2 (VEGFR2) using a structure-based drug design (SBDD) approach. X-ray crystal structure analysis suggests that interactions between 18b and amino acid residues located in the solvent region (Lys476 and Met488), and between 40a and Met529 located in the back pocket of FGFR3 may underlie the potent FGFR3 inhibitory activity and high kinase selectivity over VEGFR2.


Asunto(s)
Diseño de Fármacos , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Triazinas/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Línea Celular , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Pirimidinas/química , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/metabolismo , Relación Estructura-Actividad , Triazinas/química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo
6.
Bioorg Med Chem ; 23(13): 3351-67, 2015 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-25960322

RESUMEN

We synthesized several biaryl derivatives as PDE10A inhibitors to prevent phototoxicity of 2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline (1) and found that the energy difference between the energy-minimized conformation and the coplanar conformation of the biaryl moiety helped facilitate prediction of the phototoxic potential of biaryl compounds. Replacement of the quinoline ring of 1 with N-methyl benzimidazole increased this energy difference and prevented phototoxicity in the 3T3 NRU test. Further optimization identified 1-methyl-5-(1-methyl-3-{[4-(1-methyl-1H-benzimidazol-4-yl)phenoxy]methyl}-1H-pyrazol-4-yl)pyridin-2(1H)-one (38b). Compound 38b exhibited good selectivity against other PDEs, and oral administration of 38b improved visual-recognition memory deficit in mice at doses of 0.001 and 0.003mg/kg in the novel object recognition test. ASP9436 (sesquiphosphate of 38b) may therefore be used for the treatment of schizophrenia with a low risk of phototoxicity.


Asunto(s)
Antipsicóticos/química , Bencimidazoles/química , Inhibidores de Fosfodiesterasa/química , Hidrolasas Diéster Fosfóricas/metabolismo , Piridinas/química , Quinolinas/química , Esquizofrenia/tratamiento farmacológico , Administración Oral , Animales , Antipsicóticos/administración & dosificación , Antipsicóticos/efectos adversos , Conducta Animal/efectos de los fármacos , Bencimidazoles/administración & dosificación , Bencimidazoles/efectos adversos , Sitios de Unión , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Alucinógenos , Humanos , Masculino , Ratones , Ratones Endogámicos ICR , Reconocimiento Visual de Modelos/efectos de los fármacos , Fenciclidina , Inhibidores de Fosfodiesterasa/administración & dosificación , Inhibidores de Fosfodiesterasa/efectos adversos , Hidrolasas Diéster Fosfóricas/química , Procesos Fotoquímicos , Unión Proteica , Piridinas/administración & dosificación , Piridinas/efectos adversos , Quinolinas/administración & dosificación , Quinolinas/efectos adversos , Esquizofrenia/inducido químicamente , Esquizofrenia/enzimología , Esquizofrenia/fisiopatología , Rayos Ultravioleta
7.
Bioorg Med Chem ; 23(2): 297-313, 2015 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-25515954

RESUMEN

A novel class of phosphodiesterase 10A inhibitors with potent PDE10A inhibitory activity and reduced CYP3A4 inhibition was designed and synthesized starting from 2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline (1). Replacement of pyridine ring of 1 with N-methyl pyridone ring drastically improved CYP3A4 inhibition, and further optimization of these quinoline analogues identified 1-methyl-5-(1-methyl-3-{[4-(quinolin-2-yl)phenoxy]methyl}-1H-pyrazol-4-yl)pyridin-2(1H)-one (42b), which showed potent PDE10A inhibitory activity and a good CYP3A4 inhibition profile. A PET study with (11)C-labeled 42b indicated that 42b exhibited good brain penetration and specifically accumulated in the rodent striatum. Further, oral administration of 42b dose-dependently attenuated phencyclidine-induced hyperlocomotion in mice with an ED50 value of 2.0mg/kg and improved visual-recognition memory impairment at 0.1 and 0.3mg/kg in mice novel object recognition test.


Asunto(s)
Citocromo P-450 CYP3A/metabolismo , Inhibidores de Fosfodiesterasa/síntesis química , Hidrolasas Diéster Fosfóricas/química , Quinolinas/química , Animales , Sitios de Unión , Encéfalo/metabolismo , Citocromo P-450 CYP3A/química , Humanos , Cinética , Masculino , Ratones , Ratones Endogámicos ICR , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Actividad Motora/efectos de los fármacos , Inhibidores de Fosfodiesterasa/metabolismo , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/genética , Hidrolasas Diéster Fosfóricas/metabolismo , Tomografía de Emisión de Positrones , Estructura Terciaria de Proteína , Quinolinas/metabolismo , Quinolinas/farmacología , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/genética , Relación Estructura-Actividad
8.
Bioorg Med Chem ; 21(24): 7612-23, 2013 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-24238902

RESUMEN

A novel class of phosphodiesterase 10A (PDE10A) inhibitors with reduced CYP1A2 inhibition were designed and synthesized starting from 2-{[(1-phenyl-1H-benzimidazol-6-yl)oxy]methyl}quinoline (1). Introduction of an isopropyl group at the 2-position and a methoxy group at the 5-position of the benzimidazole ring of lead compound 1 resulted in the identification of 2-{[(2-isopropyl-5-methoxy-1-phenyl-1H-benzimidazol-6-yl)oxy]methyl}quinoline (25b), which exhibited potent PDE10A inhibitory activity with reduced CYP1A2 inhibitory activity compared to compound 1.


Asunto(s)
Bencimidazoles/farmacología , Inhibidores del Citocromo P-450 CYP1A2 , Diseño de Fármacos , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Bencimidazoles/síntesis química , Bencimidazoles/química , Cristalografía por Rayos X , Citocromo P-450 CYP1A2/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/química , Proteínas Recombinantes/metabolismo , Relación Estructura-Actividad
9.
Org Lett ; 11(12): 2531-4, 2009 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-19441795

RESUMEN

A total synthesis of brevenal is described. The pentacyclic ether core was constructed by the intramolecular allylation of alpha-acetoxy ether and subsequent ring-closing metathesis. Both of the diene side chains were introduced by Wittig olefination and a Horner-Wadsworth-Emmons reaction, respectively, in a highly stereoselective manner.


Asunto(s)
Éteres Cíclicos/síntesis química , Tiopental/análogos & derivados , Éteres Cíclicos/química , Estructura Molecular , Estereoisomerismo , Tiopental/síntesis química , Tiopental/química
10.
J Org Chem ; 72(22): 8371-5, 2007 Oct 26.
Artículo en Inglés | MEDLINE | ID: mdl-17918999

RESUMEN

The MgBr2.OEt2-mediated intramolecular allylation of a 4:1 diastereoisomeric mixture of the alpha-chloroacetoxyl ether 1a bearing the A-G/JK ring system of brevetoxin B in CH2Cl2 gave a 1:1 diastereoisomeric mixture of the trans- and cis-cyclization products 4a and 5a having the A-G/I-K ring system, while that in CH3CN afforded the trans-isomer 4a nearly as the single product. To help clarify a reason for this marked solvent effect in the cyclization of the brevetoxin B precursor, DFT computations for the starting materials, intermediates, transition states, and products were carried out. The cyclization would proceed through a carbocation intermediate 3a having sp2 flat structure (SN1 type mechanism) in CH2Cl2, in which the activation energies leading to both diastereoisomers are approximately identical, while in CH3CN alkylnitrilium salts 6a would be formed through the coordination of CH3CN to the carbocation leading to an sp3-type intermediate in which sever steric hindrance takes place in the transition state leading to the undesired diastereoisomer. The scope of this novel solvent-controlled stereoselectivity was tested for simple compounds. In small model compounds the marked solvent dependence was absent, but the model bearing two consecutive cyclic ether rings 1b exhibited a remarkable solvent effect similar to that observed in the brevetoxin B system.


Asunto(s)
Acetonitrilos/química , Éteres Cíclicos/síntesis química , Cloruro de Metileno/química , Ácidos/química , Alquilación , Ciclización , Éteres Cíclicos/química , Modelos Químicos , Conformación Molecular , Solventes/química , Estereoisomerismo
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