RESUMEN
Human dihydroorotate dehydrogenase (hDHODH), as the fourth and rate-limiting enzyme of the de novo pyrimidine synthesis pathway, is regarded as an attractive target for malignancy therapy. In the present study, a novel series of teriflunomide derivatives were designed, synthesized, and evaluated as hDHODH inhibitors. 13t was the optimal compound with promising enzymatic activity (IC50 = 16.0 nM), potent antiproliferative activity against human lymphoma Raji cells (IC50 = 7.7 nM), and excellent aqueous solubility (20.1 mg/mL). Mechanistically, 13t directly inhibited hDHODH and induced cell cycle S-phase arrest in Raji cells. The acute toxicity assay indicated a favorable safety profile of 13t. Notably, 13t displayed significant tumor growth inhibition activity with a tumor growth inhibition (TGI) rate of 81.4% at 30 mg/kg in a Raji xenograft model. Together, 13t is a promising inhibitor of hDHODH and a preclinical candidate for antitumor therapy, especially for lymphoma.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Crotonatos/química , Crotonatos/farmacología , Dihidroorotato Deshidrogenasa/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Hidroxibutiratos/química , Hidroxibutiratos/farmacología , Neoplasias/tratamiento farmacológico , Nitrilos/química , Nitrilos/farmacología , Toluidinas/química , Toluidinas/farmacología , Antineoplásicos/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Crotonatos/síntesis química , Inhibidores Enzimáticos/síntesis química , Humanos , Hidroxibutiratos/síntesis química , Neoplasias/patología , Nitrilos/síntesis química , Relación Estructura-Actividad , Toluidinas/síntesis químicaRESUMEN
The two isotopomers of teriflunomide were synthesized starting from isotopically stable-labeled stocks of [13 C]potassium cyanide and [1-13 C]ethyl bromoacetate. The two 13 C-labeled compounds 1a, b were applied in several NMR studies to study the E/Z ratio in different matrices. In a solution, such as dimethyl sulfoxide (DMSO), a dynamic equilibrium between E/Z-isomers (ratio of 8:92) was determined by initial 13 C-carbon NMR experiments. To get insights into the E/Z ratio of teriflunomide under in vivo conditions, advanced heteronuclear NMR (heteronuclear Overhauser effect spectroscopy [HOESY]) in D2 O and mixtures of D2 O/plasma were performed. Whereas NMR experiments in mixtures of water and plasma failed owing to extreme line broadening, NMR spectra in water at pH 7.4 showed only the Z-isomer.
Asunto(s)
Crotonatos/síntesis química , Hidroxibutiratos/síntesis química , Marcaje Isotópico/métodos , Nitrilos/síntesis química , Toluidinas/síntesis química , Acetatos/química , Isótopos de Carbono/química , Hidrocarburos Bromados/química , Isomerismo , Espectroscopía de Resonancia Magnética/métodos , Cianuro de Potasio/químicaRESUMEN
γ-Cyclodextrin-based metal-organic framework (γCD-MOF) crystals were successfully synthesized using a vapor diffusion method. An applicability of γCD-MOF for encapsulation of immunosuppressive disease-modifying antirheumatic drug leflunomide (LEF) was examined. Loading of LEF in γCD-MOF was performed by impregnation and co-crystallization. The empty and loaded γCD-MOFs were characterized using X-ray powder diffraction, N2 adsorption/desorption, thermogravimetric analysis, 1H NMR and FTIR spectroscopy. It was shown that in the presence of γCD-MOF leflunomide is transformed into its pharmacologically active form - teriflunomide that can be also applied alone in the treatment of multiple sclerosis. It was demonstrated that teriflunomide released from γCD-MOF has improved pharmacologically relevant properties such as solubility, dissolution rate and membrane permeability. It can be proposed that γCD-MOF can be considered as novel strategy for delivery of leflunomide.
Asunto(s)
Antirreumáticos/química , Crotonatos/síntesis química , Leflunamida/química , Estructuras Metalorgánicas/química , Profármacos/química , Toluidinas/síntesis química , gamma-Ciclodextrinas/química , Liberación de Fármacos , Hidroxibutiratos , Cinética , Estructuras Metalorgánicas/síntesis química , Nitrilos , Oxidación-Reducción , Permeabilidad , Porosidad , Solubilidad , gamma-Ciclodextrinas/síntesis químicaRESUMEN
Using the patch-clamp method in the whole-cell configuration, we showed that the new derivatives of 2-aminothiophene-3-carboxylic acid, which were synthesized by us earlier, can both block (compound 1) and potentiate (compound 2) calcium-activated chloride currents in single rat cerebellar Purkinje cells.
Asunto(s)
Canales de Cloruro/metabolismo , Potenciales de la Membrana/efectos de los fármacos , Células de Purkinje/metabolismo , Toluidinas , Animales , Células Cultivadas , Ratas , Toluidinas/síntesis química , Toluidinas/química , Toluidinas/farmacologíaRESUMEN
Diazocoupling reaction of curcumin with different diazonium salts of p-toluidine, 2-aminopyridine, and 4-aminoantipyrine in pyridine yielded the arylhydrazones 2a-c. Arylhydrazone of p-toluidine reacted with urea, thiourea, and guanidine nitrate to produce 5,6-dihydropyrimidines. Further reaction of 2a with 2,3-diaminopyrdine in sodium ethoxide solution yielded 1H-pyrido[2,3-b][1,4]diazepine derivative. Bis(2,5-dihydroisoxazole) is obtained from the reaction of 2a with hydroxylamine hydrochloride, while its reactions with hydrazines afforded the respective 4,5-dihydro-1H-pyrazoles. The target compounds were evaluated as antioxidant and antibacterial agents. The tested compounds showed good to moderate activities compared to ascorbic acid and chloramphenicol, respectively.
Asunto(s)
Antibacterianos/farmacología , Antioxidantes/farmacología , Curcumina/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Aminopiridinas/síntesis química , Aminopiridinas/química , Ampirona/síntesis química , Ampirona/química , Antibacterianos/síntesis química , Antibacterianos/química , Antioxidantes/síntesis química , Antioxidantes/química , Ácido Ascórbico/farmacología , Cloranfenicol/farmacología , Curcumina/análogos & derivados , Curcumina/síntesis química , Curcumina/química , Compuestos de Diazonio/síntesis química , Compuestos de Diazonio/química , Bacterias Gramnegativas/patogenicidad , Bacterias Grampositivas/patogenicidad , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-Actividad , Toluidinas/síntesis química , Toluidinas/químicaRESUMEN
Salicylidene (4-aminotoluene-3-sulfonic acid) Schiff base ligand H(2)L, and its binary and ternary Co(II), Ni(II), Cu(II) and Zn(II) complexes using 8-hydroxyquinoline (8-HOqu) and 2-aminopyridine (2-Ampy) as secondary ligands have been synthesised and characterized via elemental analysis, spectral data (IR, (1)H NMR, mass and solid reflectance), molar conductance, magnetic moment, TG-DSC measurements and XRPD analysis. Correlation of all spectroscopic data suggest that H(2)L ligand acts as monoanionic terdentate ligand with ONO sites coordinating to the metal ions via deprotonated phenolic-O, azomethine-N and sulfonate-O while 2-Ampy behaves as a neutral monodentate ligand via amino group-N and 8-HOqu behaves as a monoanionic bidentate ligand through the ring-N and deprotonated phenolic-O. The thermal behavior of these complexes shows that the coordinated water molecules were eliminated from the complexes at relatively higher temperatures than the hydrated water and there are two routes in removal of coordinated water molecules. All complexes have mononuclear structure and the tetrahedral, square planar or an octahedral geometry have been proposed. The ligand and its complexes have been screened for their antimicrobial activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Salmonella typhimurium, Candida albicans and Aspergillus fumigatus. Among the synthesised compounds, the binary and ternary Ni(II) complexes, (2, 8 and 10) and ternary Zn(II) complex, (12) were found to be very effective against Candida albicans and Bacillus subtilis than all other complexes with MICs of 2 and 8 µg/mL, respectively.
Asunto(s)
Antiinfecciosos/química , Cobalto/química , Cobre/química , Níquel/química , Bases de Schiff/química , Ácidos Sulfónicos/química , Zinc/química , Aminopiridinas/síntesis química , Aminopiridinas/química , Aminopiridinas/farmacología , Antiinfecciosos/síntesis química , Antiinfecciosos/farmacología , Bacterias/efectos de los fármacos , Infecciones Bacterianas/tratamiento farmacológico , Cobalto/farmacología , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Cobre/farmacología , Hongos/efectos de los fármacos , Humanos , Ligandos , Micosis/tratamiento farmacológico , Níquel/farmacología , Oxiquinolina/síntesis química , Oxiquinolina/química , Oxiquinolina/farmacología , Bases de Schiff/síntesis química , Bases de Schiff/farmacología , Análisis Espectral , Ácidos Sulfónicos/síntesis química , Ácidos Sulfónicos/farmacología , Toluidinas/síntesis química , Toluidinas/química , Toluidinas/farmacología , Zinc/farmacologíaRESUMEN
Multiple sclerosis (MS) often results in chronic inflammatory and autoimmune disorders, and recent developments in understanding the disease pathogenesis has lead to newer therapeutic options for the treatment of the disease. The development of small molecule drugs with improved efficacy, better tolerability, and oral administration has received a new impetus with the discovery of newer classes of drugs. In this review, we have summarized the hitherto known synthetic strategies of fingolimod, laquinimod, cladribine, and teriflunomide reported in the literature which are the key small molecules and the first oral drug candidates for MS in various stages of clinical development or have been launched in the market.
Asunto(s)
Cladribina/uso terapéutico , Crotonatos/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Glicoles de Propileno/uso terapéutico , Quinolonas/uso terapéutico , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Esfingosina/análogos & derivados , Toluidinas/uso terapéutico , Cladribina/síntesis química , Cladribina/química , Crotonatos/síntesis química , Crotonatos/química , Clorhidrato de Fingolimod , Humanos , Hidroxibutiratos , Estructura Molecular , Nitrilos , Glicoles de Propileno/síntesis química , Glicoles de Propileno/química , Quinolonas/síntesis química , Quinolonas/química , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Esfingosina/síntesis química , Esfingosina/química , Esfingosina/uso terapéutico , Toluidinas/síntesis química , Toluidinas/químicaRESUMEN
Inhibitors of hypoxia-inducible factor 1 (HIF-1) represent promising anticancer therapeutics. We have identified a series of potent toluidinesulfonamide HIF-1 inhibitors. However, the series was threatened by a potential liability to inhibit CYP2C9 which could cause dangerous drug-drug interactions when being coadministered with other drugs. We used structure-activity data from the PubChem database to develop a topomer CoMFA model that guided the design of novel sulfonamides with high selectivity for HIF-1 over CYP2C9 inhibition.
Asunto(s)
Hidrocarburo de Aril Hidroxilasas/antagonistas & inhibidores , Diseño de Fármacos , Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Sulfonamidas/química , Toluidinas/química , Hidrocarburo de Aril Hidroxilasas/química , Hidrocarburo de Aril Hidroxilasas/metabolismo , Citocromo P-450 CYP2C9 , Bases de Datos Factuales , Interacciones Farmacológicas , Humanos , Factor 1 Inducible por Hipoxia/metabolismo , Ligandos , Estructura Molecular , Relación Estructura-Actividad Cuantitativa , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Toluidinas/síntesis química , Toluidinas/farmacologíaRESUMEN
Poly(ortho-toluidine) (POT)-gold (Au) and palladium (Pd) composite nanospheres were successfully synthesized by the reaction of o-toluidine with the corresponding metal (Au or Pd) colloidal solution through self-assembly process in the presence of dodecylbenzenesulfonic acid (DBSA), which acts as both a dopant and surfactant, and ammonium peroxydisulfate as an oxidizing agent. The composites (POT-DBSA/Au or Pd) were characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM), X-ray diffraction (XRD), thermogravimetric analysis (TGA), Fourier transform infrared (FTIR) spectroscopy, UV-Visible (UV-Vis) spectroscopy, and electrical conductivity measurements. TEM images of the nanocomposites reveal that metal (Au or Pd) nanoparticles were well dispersed on POT spheres. TGA and XRD results show that the composites exhibit high thermal stability and are more crystalline compared with pristine POT. It was found that the electrical conductivity of the POT-DBSA/Au or Pd composites is 2 orders of magnitude higher than that of pristine polymer. Also, the POT-DBSA/Pd composite exhibits magnetic property. The formation mechanism of the POT-DBSA/Au or Pd composite nanosphere is discussed.
Asunto(s)
Oro/química , Nanopartículas del Metal/química , Nanosferas/química , Nanotecnología/métodos , Paladio/química , Toluidinas/química , Dextranos/química , Microscopía Electrónica de Rastreo , Microscopía Electrónica de Transmisión , Oxígeno/química , Polímeros/química , Espectrofotometría Ultravioleta , Espectroscopía Infrarroja por Transformada de Fourier , Sulfonamidas/química , Termogravimetría/métodos , Toluidinas/síntesis química , Difracción de Rayos XRESUMEN
[reaction: see text] N,N-Di(6-azulenyl)-p-toluidine (1a) and N,N,N',N'-tetra(6-azulenyl)-p-phenylenediamine (2a) and their derivatives with 1,3-bis(ethoxycarbonyl) substituents on each 6-azulenyl group (1b and 2b) were prepared by Pd-catalyzed amine azulenylation and characterized as a study into new aromatic amines for multistage amphoteric redox materials. The redox behavior of each compound was characterized by cyclic voltammetry. These compounds undergo facile reduction to stable anion radicals and dianion diradicals owing to the resonance stabilization between the 6-azulenyl groups and exhibit electrochemical oxidation depending on the amine subunits. The ESR measurement of anion radicals and a dianion diradical generated by the electrochemical reduction of amine 1b and diamine 2b revealed that the unpaired electron of these radicals delocalizes over the entire azulene ring including the central nitrogen atoms. UV-vis spectral analysis of amines 1a,b and diamines 2a,b, taken during the electrochemical reduction, exhibited a gradual decrease of the absorption bands of the neutral species along with an increase of the new absorption maxima at 625, 605, 640, and 610 nm, respectively, with the development of well-defined isosbestic points at 502, 562, 478, and 545 nm, respectively. As indicated by a combined ESR and UV-vis spectral study, the species giving rise to the new absorption maxima are concluded to be the generation of anion radicals and dianion diradicals of aromatic amines and diamines with high thermodynamic stability.
Asunto(s)
Aminas/síntesis química , Cicloheptanos/química , Fenilendiaminas/síntesis química , Toluidinas/síntesis química , Azulenos , Modelos Químicos , Modelos Moleculares , Estructura Molecular , Oxidación-Reducción , Toluidinas/químicaAsunto(s)
Toluidinas/toxicidad , Animales , Pruebas de Carcinogenicidad , Carcinógenos/síntesis química , Carcinógenos/química , Carcinógenos/farmacología , Carcinógenos/toxicidad , Colorantes/síntesis química , Colorantes/química , Colorantes/farmacología , Colorantes/toxicidad , Exposición a Riesgos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/legislación & jurisprudencia , Femenino , Guías como Asunto , Humanos , Masculino , Ratones , Modelos Biológicos , Ratas , Toluidinas/síntesis química , Toluidinas/química , Toluidinas/farmacologíaAsunto(s)
Colorantes de Rosanilina/toxicidad , Toluidinas/toxicidad , Animales , Pruebas de Carcinogenicidad , Carcinógenos/síntesis química , Carcinógenos/química , Carcinógenos/farmacología , Carcinógenos/toxicidad , Colorantes/síntesis química , Colorantes/química , Colorantes/farmacología , Colorantes/toxicidad , Exposición a Riesgos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/legislación & jurisprudencia , Femenino , Guías como Asunto , Humanos , Masculino , Ratones , Modelos Biológicos , Ratas , Colorantes de Rosanilina/síntesis química , Colorantes de Rosanilina/química , Colorantes de Rosanilina/farmacología , Toluidinas/síntesis química , Toluidinas/química , Toluidinas/farmacologíaAsunto(s)
Carcinógenos/toxicidad , Toluidinas/toxicidad , Animales , Pruebas de Carcinogenicidad , Carcinógenos/síntesis química , Carcinógenos/química , Carcinógenos/farmacología , Colorantes/síntesis química , Colorantes/química , Colorantes/farmacología , Colorantes/toxicidad , Cricetinae , Femenino , Regulación Gubernamental , Guías como Asunto , Humanos , Masculino , Ratones , Modelos Biológicos , Exposición Profesional/efectos adversos , Exposición Profesional/legislación & jurisprudencia , Ratas , Sales (Química)/síntesis química , Sales (Química)/química , Sales (Química)/farmacología , Sales (Química)/toxicidad , Toluidinas/síntesis química , Toluidinas/química , Toluidinas/farmacología , Estados UnidosRESUMEN
A series of cyano- and carboxyborane adducts of cyclohexylamines and toluidines were shown to be cytotoxic towards suspended single cell tumors. The carboxyborane adducts of cyclohexylamine were more potent than the cyanoborane adducts of cyclohexylamine or any of the toluidine derivatives. A number of the compounds were active at 8 mg/kg/day i.p. in the Ehrlich ascites carcinoma screen in vivo. The mode of action study with N-methylcyclohexylaminecyanoborane 10 in L-1210 lymphoid leukemia cells showed that RNA synthesis was markedly reduced followed by DNA synthesis. Purine de novo synthesis was suppressed at PRPP-amido transferase, IMP dehydrogenase, and dihydrofolate reductase enzyme sites. The agent also interfered with DNA template activity causing reduction of DNA polymerase alpha, and RNA polymerase I, II and III activities. The d[NTP] pools were marginally reduced while DNA viscosity was reduced and DNA fragmentation occurred.
Asunto(s)
Antineoplásicos/síntesis química , Boranos/síntesis química , Ciclohexilaminas/síntesis química , Toluidinas/síntesis química , Animales , Antineoplásicos/farmacología , Boranos/farmacología , Fenómenos Químicos , Química Física , Ciclohexilaminas/farmacología , ADN de Neoplasias/biosíntesis , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Espectroscopía de Resonancia Magnética , Ratones , Proteínas de Neoplasias/biosíntesis , ARN Neoplásico/biosíntesis , Ratas , Toluidinas/farmacología , Células Tumorales CultivadasAsunto(s)
Carcinógenos , Colorantes/toxicidad , Neoplasias/inducido químicamente , Enfermedades Profesionales/inducido químicamente , Toluidinas/toxicidad , Animales , Fenómenos Químicos , Química , Colorantes/síntesis química , Colorantes/farmacocinética , Femenino , Humanos , Masculino , Ratones , Mutágenos , Ratas , Toluidinas/síntesis química , Toluidinas/farmacocinéticaRESUMEN
The synthesis and pharmacological evaluation of primary and tertiary aminoxylidides with the amino group in the 2-7 position of the acyl chain are described. 2,6-Xylidine was acylated with haloacyl halides and converted to the target compounds by direct amination or by the Gabriel procedure. Alternatively, 2,6-xylidine was coupled with keto acids, and the ketoxylidides were converted to the amines by reductive amination. The target compounds were evaluated in mice both for antiarrhythmic efficacy against chloroform-induced tachycardia and for central nervous system toxicity. Experimentally determined values of partition coefficients and pKa values were used for quantitative structure-activity analyses. While the antiarrhythmic activity could be described as a function of log P alone, the CNS toxicity was best described as a function of both log P and pKa. The results suggest that antiarrhythmic potency can be increased by increasing lipophilicity, while the therapeutic index can be improved by increasing the pKa.
Asunto(s)
Antiarrítmicos/síntesis química , Toluidinas/síntesis química , Animales , Sistema Nervioso Central/efectos de los fármacos , Fenómenos Químicos , Química , Femenino , Ratones , Relación Estructura-ActividadAsunto(s)
Compuestos de Aminobifenilo/toxicidad , Compuestos de Anilina/toxicidad , Mutágenos , Toluidinas/toxicidad , Compuestos de Aminobifenilo/síntesis química , Compuestos de Anilina/síntesis química , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/genética , Relación Estructura-Actividad , Toluidinas/síntesis químicaRESUMEN
The accelerating activity of N,N-substituted aminoethyl methacrylates on the curing of methyl methacrylate and composite resins with benzoyl peroxide is somewhat smaller than that of dimethyl-p-toluidine. Tesins cured with aminoethyl methacrylates containing a p-tolyl and 3,5-xylyl substituent on the nitrogen atom turned approximately the same color in ultraviolet light as resins cured with dimethyl-p-toluidinemthe incorporation of the predominant part of an unsaturated tertiary amine into polymer chains reduces to a minimum the possibility of its diffusion from the resin into the surrounding tissue.