RESUMO
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.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Crotonatos/química , Crotonatos/farmacologia , Di-Hidro-Orotato Desidrogenase/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Hidroxibutiratos/química , Hidroxibutiratos/farmacologia , Neoplasias/tratamento farmacológico , Nitrilas/química , Nitrilas/farmacologia , Toluidinas/química , Toluidinas/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Crotonatos/síntese química , Inibidores Enzimáticos/síntese química , Humanos , Hidroxibutiratos/síntese química , Neoplasias/patologia , Nitrilas/síntese química , Relação Estrutura-Atividade , Toluidinas/síntese químicaRESUMO
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.
Assuntos
Crotonatos/síntese química , Hidroxibutiratos/síntese química , Marcação por Isótopo/métodos , Nitrilas/síntese química , Toluidinas/síntese química , Acetatos/química , Isótopos de Carbono/química , Hidrocarbonetos Bromados/química , Isomerismo , Espectroscopia de Ressonância Magnética/métodos , Cianeto de Potássio/químicaRESUMO
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.
Assuntos
Antirreumáticos/química , Crotonatos/síntese química , Leflunomida/química , Estruturas Metalorgânicas/química , Pró-Fármacos/química , Toluidinas/síntese química , gama-Ciclodextrinas/química , Liberação Controlada de Fármacos , Hidroxibutiratos , Cinética , Estruturas Metalorgânicas/síntese química , Nitrilas , Oxirredução , Permeabilidade , Porosidade , Solubilidade , gama-Ciclodextrinas/síntese químicaRESUMO
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.
Assuntos
Canais de Cloreto/metabolismo , Potenciais da Membrana/efeitos dos fármacos , Células de Purkinje/metabolismo , Toluidinas , Animais , Células Cultivadas , Ratos , Toluidinas/síntese química , Toluidinas/química , Toluidinas/farmacologiaRESUMO
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.
Assuntos
Antibacterianos/farmacologia , Antioxidantes/farmacologia , Curcumina/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Aminopiridinas/síntese química , Aminopiridinas/química , Ampirona/síntese química , Ampirona/química , Antibacterianos/síntese química , Antibacterianos/química , Antioxidantes/síntese química , Antioxidantes/química , Ácido Ascórbico/farmacologia , Cloranfenicol/farmacologia , Curcumina/análogos & derivados , Curcumina/síntese química , Curcumina/química , Compostos de Diazônio/síntese química , Compostos de Diazônio/química , Bactérias Gram-Negativas/patogenicidade , Bactérias Gram-Positivas/patogenicidade , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Toluidinas/síntese química , Toluidinas/químicaRESUMO
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.
Assuntos
Cladribina/uso terapêutico , Crotonatos/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Propilenoglicóis/uso terapêutico , Quinolonas/uso terapêutico , Bibliotecas de Moléculas Pequenas/uso terapêutico , Esfingosina/análogos & derivados , Toluidinas/uso terapêutico , Cladribina/síntese química , Cladribina/química , Crotonatos/síntese química , Crotonatos/química , Cloridrato de Fingolimode , Humanos , Hidroxibutiratos , Estrutura Molecular , Nitrilas , Propilenoglicóis/síntese química , Propilenoglicóis/química , Quinolonas/síntese química , Quinolonas/química , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Esfingosina/síntese química , Esfingosina/química , Esfingosina/uso terapêutico , Toluidinas/síntese química , Toluidinas/químicaRESUMO
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.
Assuntos
Anti-Infecciosos/química , Cobalto/química , Cobre/química , Níquel/química , Bases de Schiff/química , Ácidos Sulfônicos/química , Zinco/química , Aminopiridinas/síntese química , Aminopiridinas/química , Aminopiridinas/farmacologia , Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Bactérias/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Cobalto/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Cobre/farmacologia , Fungos/efeitos dos fármacos , Humanos , Ligantes , Micoses/tratamento farmacológico , Níquel/farmacologia , Oxiquinolina/síntese química , Oxiquinolina/química , Oxiquinolina/farmacologia , Bases de Schiff/síntese química , Bases de Schiff/farmacologia , Análise Espectral , Ácidos Sulfônicos/síntese química , Ácidos Sulfônicos/farmacologia , Toluidinas/síntese química , Toluidinas/química , Toluidinas/farmacologia , Zinco/farmacologiaRESUMO
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.
Assuntos
Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores , Desenho de Fármacos , Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Sulfonamidas/química , Toluidinas/química , Hidrocarboneto de Aril Hidroxilases/química , Hidrocarboneto de Aril Hidroxilases/metabolismo , Citocromo P-450 CYP2C9 , Bases de Dados Factuais , Interações Medicamentosas , Humanos , Fator 1 Induzível por Hipóxia/metabolismo , Ligantes , Estrutura Molecular , Relação Quantitativa Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Toluidinas/síntese química , Toluidinas/farmacologiaRESUMO
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.
Assuntos
Ouro/química , Nanopartículas Metálicas/química , Nanosferas/química , Nanotecnologia/métodos , Paládio/química , Toluidinas/química , Dextranos/química , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Oxigênio/química , Polímeros/química , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Sulfonamidas/química , Termogravimetria/métodos , Toluidinas/síntese química , Difração de Raios XRESUMO
[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.
Assuntos
Aminas/síntese química , Cicloeptanos/química , Fenilenodiaminas/síntese química , Toluidinas/síntese química , Azulenos , Modelos Químicos , Modelos Moleculares , Estrutura Molecular , Oxirredução , Toluidinas/químicaAssuntos
Carcinógenos/toxicidade , Toluidinas/toxicidade , Animais , Testes de Carcinogenicidade , Carcinógenos/síntese química , Carcinógenos/química , Carcinógenos/farmacologia , Corantes/síntese química , Corantes/química , Corantes/farmacologia , Corantes/toxicidade , Cricetinae , Feminino , Regulamentação Governamental , Guias como Assunto , Humanos , Masculino , Camundongos , Modelos Biológicos , Exposição Ocupacional/efeitos adversos , Exposição Ocupacional/legislação & jurisprudência , Ratos , Sais/síntese química , Sais/química , Sais/farmacologia , Sais/toxicidade , Toluidinas/síntese química , Toluidinas/química , Toluidinas/farmacologia , Estados UnidosAssuntos
Toluidinas/toxicidade , Animais , Testes de Carcinogenicidade , Carcinógenos/síntese química , Carcinógenos/química , Carcinógenos/farmacologia , Carcinógenos/toxicidade , Corantes/síntese química , Corantes/química , Corantes/farmacologia , Corantes/toxicidade , Exposição Ambiental/efeitos adversos , Exposição Ambiental/legislação & jurisprudência , Feminino , Guias como Assunto , Humanos , Masculino , Camundongos , Modelos Biológicos , Ratos , Toluidinas/síntese química , Toluidinas/química , Toluidinas/farmacologiaAssuntos
Corantes de Rosanilina/toxicidade , Toluidinas/toxicidade , Animais , Testes de Carcinogenicidade , Carcinógenos/síntese química , Carcinógenos/química , Carcinógenos/farmacologia , Carcinógenos/toxicidade , Corantes/síntese química , Corantes/química , Corantes/farmacologia , Corantes/toxicidade , Exposição Ambiental/efeitos adversos , Exposição Ambiental/legislação & jurisprudência , Feminino , Guias como Assunto , Humanos , Masculino , Camundongos , Modelos Biológicos , Ratos , Corantes de Rosanilina/síntese química , Corantes de Rosanilina/química , Corantes de Rosanilina/farmacologia , Toluidinas/síntese química , Toluidinas/química , Toluidinas/farmacologiaRESUMO
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.
Assuntos
Antineoplásicos/síntese química , Boranos/síntese química , Cicloexilaminas/síntese química , Toluidinas/síntese química , Animais , Antineoplásicos/farmacologia , Boranos/farmacologia , Fenômenos Químicos , Físico-Química , Cicloexilaminas/farmacologia , DNA de Neoplasias/biossíntese , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Proteínas de Neoplasias/biossíntese , RNA Neoplásico/biossíntese , Ratos , Toluidinas/farmacologia , Células Tumorais CultivadasAssuntos
Carcinógenos , Corantes/toxicidade , Neoplasias/induzido quimicamente , Doenças Profissionais/induzido quimicamente , Toluidinas/toxicidade , Animais , Fenômenos Químicos , Química , Corantes/síntese química , Corantes/farmacocinética , Feminino , Humanos , Masculino , Camundongos , Mutagênicos , Ratos , Toluidinas/síntese química , Toluidinas/farmacocinéticaRESUMO
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.
Assuntos
Antiarrítmicos/síntese química , Toluidinas/síntese química , Animais , Sistema Nervoso Central/efeitos dos fármacos , Fenômenos Químicos , Química , Feminino , Camundongos , Relação Estrutura-AtividadeAssuntos
Compostos de Aminobifenil/toxicidade , Compostos de Anilina/toxicidade , Mutagênicos , Toluidinas/toxicidade , Compostos de Aminobifenil/síntese química , Compostos de Anilina/síntese química , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/genética , Relação Estrutura-Atividade , Toluidinas/síntese químicaRESUMO
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.