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1.
J Org Chem ; 86(19): 13420-13445, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34546053

RESUMO

An efficient diastereoselective route is developed to get access to novel spiropyrrolo[1,2-a]isoquinoline-oxindole skeletons by a one-pot three-component [3 + 2] cycloaddition reaction of (Z)-5-arylidene-1,3-thiazolidine-2,4-diones, isatin derivatives, and 1,2,3,4-tetrahydroisoquinoline (THIQ). Interestingly, the regioselectivity of the reaction is both temperature- and solvent-dependent, allowing the synthesis of two regioisomeric endo-dispiropyrrolo[2,1-a]isoquinolineoxindoles in excellent yield. Unprecedentedly, each isomeric dispiropyrrolo[2,1-a]isoquinolineoxindole endured retro-1,3-dipolar cycloaddition/recycloaddition reactions under thermal or catalytic conditions to regenerate the corresponding regioisomeric counterpart. In addition, DFT calculations were performed at the M062X/6-31++g(d,p) level of theory to unravel the origin of the reversal of regioselectivity and endo-stereoselectivity of the title 1,3-dipolar cycloaddition reactions. Upon treatment of Isatin, THIQ with (Z)-4-arylidene-5-thioxo-thiazolidin-2-ones as dipolarophiles, unusual rhodanine analogues were formed, along with smaller amounts of a dispirooxindole-piperazine. The structure and the relative configuration of these N-heterocycles were unambiguously assigned by spectroscopic techniques and confirmed by four single-crystal structures. In vitro and in vivo studies reveal that the novel rhodanine derivatives exert antidiabetic activity. The binding affinity with the active site of the enzyme α-amylase was studied by molecular docking. Furthermore, the bioavailability assessed through virtual ADME parameters (Absorption, Distribution, Metabolism, Elimination pharmacokinetics) and the excellent fit with the Lipinski and Veber rules predict good drug-likeness properties for a bromo-substituted 2-sulfanylidene-1,3-thiazolidin-4-one.


Assuntos
Rodanina , Reação de Cicloadição , Hipoglicemiantes , Isoquinolinas , Simulação de Acoplamento Molecular
2.
J Enzyme Inhib Med Chem ; 36(1): 1996-2009, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34525898

RESUMO

Microtubule dynamics are crucial for multiple cell functions, and cancer cells are particularly sensitive to microtubule-modulating agents. Here, we describe the design and synthesis of a series of (Z)-2-(5-benzylidene-4-oxo-2-thioxothiazolidin-3-yl)-N-phenylacetamide derivatives and evaluation of their microtubule-modulating and anticancer activities in vitro. Proliferation assays identified I20 as the most potent of the antiproliferative compounds, with 50% inhibitory concentrations ranging from 7.0 to 20.3 µM with A549, PC-3, and HepG2 human cancer cell lines. Compound I20 also disrupted cancer A549 cell migration in a concentration-dependent manner. Immunofluorescence microscopy, transmission electron microscopy, and tubulin polymerisation assays suggested that compound I20 promoted protofilament assembly. In support of this possibility, computational docking studies revealed a strong interaction between compound I20 and tubulin Arg ß369, which is also the binding site for the anticancer drug Taxol. Our results suggest that (Z)-2-(5-benzylidene-4-oxo-2-thioxothiazolidin-3-yl)-N-phenylacetamide derivatives could have utility for the development of microtubule-stabilising therapeutic agents.


Assuntos
Acetatos/farmacologia , Amidas/farmacologia , Antineoplásicos/farmacologia , Descoberta de Drogas , Microtúbulos/efeitos dos fármacos , Rodanina/farmacologia , Moduladores de Tubulina/farmacologia , Células A549 , Acetatos/síntese química , Acetatos/química , Amidas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Microtúbulos/metabolismo , Estrutura Molecular , Polimerização/efeitos dos fármacos , Rodanina/análogos & derivados , Rodanina/química , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
3.
J Hazard Mater ; 419: 126449, 2021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34323715

RESUMO

A simple rhodanine derived fluorophoric unit has been designed for selective detection of Ag+ and I- ions in DMSO-H2O medium. The sensor R1 showed an obvious "turn-on" fluorescence response toward Ag+ due to the inhibition of both C-N single bond free rotation, internal charge transfer (ICT) and the formation of chelation enhanced fluorescence (CHEF) effects. The fluorescence quantum yield (Φ) was increased from 0.0013 to 0.032 for receptor R1 upon the Ag+-complexation. In addition, the 1:1 complexing stoichiometry was employed based on Job's plot analysis with detection limit of 24.23 × 10-7 M. Conversely, receptor R1+Ag+ particularly detects I- ion over other co-existing anions by the "turn-off" fluorescence response due to the formation of AgI, displacing the receptor R1 with the quantum yield of 0.0014. The detection limit was calculated to be 22.83 × 10-7 M. The sensing behaviour of receptor R1 toward Ag+ was also supported by density functional theory (DFT) calculations. Moreover, the sensing ability of reported receptor R1 could be exercised in multifarious applications like paper strip, silica-supported analysis, staining test for latent finger print, logical behaviour, smartphone-assisted quantitative detection and real water samples studies.


Assuntos
Rodanina , Prata , Teoria da Densidade Funcional , Corantes Fluorescentes , Iodetos , Íons
4.
J Microbiol Biotechnol ; 31(6): 867-874, 2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-33820886

RESUMO

Epalrestat (EPS) is a brain penetrant aldose reductase inhibitor, an approved drug currently used for the treatment of diabetic neuropathy. At near-plasma concentration, EPS induces glutathione biosynthesis, which in turn reduces oxidative stress in the neuronal cells. In this study, we found that EPS reduces neurodegeneration by inhibiting reactive oxygen species (ROS)-induced oxidative injury, mitochondrial membrane damage, apoptosis and tauopathy. EPS treatment up to 50 µM did not show any toxic effect on SH-SY5Y cell line (neuroblastoma cells). However, we observed toxic effect at a concentration of 100 µM and above. At 50 µM concentration, EPS showed better antioxidant activity against H2O2 (100 µM)-induced cytotoxicity, ROS formation and mitochondrial membrane damage in retinoic acid-differentiated SH-SY5Y cell line. Furthermore, our study revealed that 50 µM of EPS concentration reduced the glycogen synthase kinase-3 ß (GSK3-ß) expression and total tau protein level in H2O2 (100 µM)-treated cells. Findings from this study confirms the therapeutic efficacy of EPS on regulating Alzheimer's disease (AD) by regulating GSK3-ß and total tau proteins phosphorylation, which helped to restore the cellular viability. This process could also reduce toxic fibrillary tangle formation and disease progression of AD. Therefore, it is our view that an optimal concentration of EPS therapy could decrease AD pathology by reducing tau phosphorylation through regulating the expression level of GSK3-ß.


Assuntos
Peróxido de Hidrogênio/efeitos adversos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Rodanina/análogos & derivados , Tiazolidinas/farmacologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Rodanina/farmacologia , Tretinoína/farmacologia , Proteínas tau/metabolismo
5.
Neurotox Res ; 39(3): 588-597, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33713301

RESUMO

Aldose reductase (AR) catalyzes the conversion of glucose to sorbitol in a NADPH-dependent reaction, thereby increasing the production of reactive oxygen species (ROS). Since AR activation is linked to redox dysregulation and cell damage in neurodegenerative diseases, AR inhibitors (ARIs) constitute promising therapeutic tools for the treatment of these disorders. Among these compounds, the novel substituted triazinoindole derivatives cemtirestat (CMTI) and COTI, as well as the clinically employed epalrestat (EPA) and the pyridoindole-antioxidant stobadine (STB), were tested in both PC12 cells and BV2 microglia exposed to four different neurotoxic models. These include (1) oxidative stress with hydrogen peroxide (H2O2), (2) mitochondrial complex IV inhibition with NaN3, (3) endoplasmic reticulum-stress and lipotoxicity induced by palmitic acid/bovine serum albumin (PAM/BSA), and (4) advanced carbonyl compound lipotoxicity by 4-hydroxynonenal (4-HNE). All toxic compounds decreased cell viability and increased ROS formation in both PC12 and BV2 cells in a concentration-dependent manner (1-1000 µM; NaN3 < H2O2≈PAM/BSA < 4-HNE). In PC12 cells, EPA increased cell viability in all toxic models only at 1 µM, whereas CMTI restored baseline viability in all toxic models. COTI afforded protection against lipotoxicity, while STB only prevented H2O2-induced toxicity. Except for the 4-HNE model, EPA prevented ROS generation in all other toxic models, whereas CMTI, COTI, and STB prevented ROS production in all toxic models. In BV2 cells, EPA and CMTI restored baseline cell viability in all toxic models tested, while COTI and STB did not prevent the loss of viability in the NaN3 model. All ARIs and STB efficiently prevented ROS formation in all toxic models in a concentration-independent manner. The differential protective effects evoked by the novel ARIs and STB on the toxic models tested herein provide novel and relevant comparative evidence for the design of specific therapeutic strategies against neurodegenerative events associated with neurological disorders.


Assuntos
Aldeído Redutase/antagonistas & inibidores , Antioxidantes/farmacologia , Carbolinas/farmacologia , Inibidores Enzimáticos/farmacologia , Microglia/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Rodanina/análogos & derivados , Tiazolidinas/farmacologia , Aldeído Redutase/metabolismo , Animais , Antioxidantes/química , Carbolinas/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Indóis/química , Indóis/farmacologia , Camundongos , Microglia/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/fisiologia , Células PC12 , Piridonas/química , Piridonas/farmacologia , Ratos , Rodanina/química , Rodanina/farmacologia , Tiazolidinas/química
6.
Bioorg Med Chem Lett ; 41: 127981, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33766767

RESUMO

Increasing evidences demonstrated that PRL-3 was associated with metastatic potential in a variety of cancers including CRC, gastric cancer, ovarian cancer and so on. PRL-3 knock down inhibited the development of metastasis by reducing the size of primary tumors and inhibiting the invasion and growth of cancer cells. Therefore, PRL-3 is a promising diagnostic marker and therapeutic target in tumors. So far, only several PRL-3 inhibitors have been reported. In this study, six rhodanine derivatives were synthesized and characterized. The compounds were evaluated against tyrosine phosphatase PRL-3. Among these compounds, 5-(5-chloro-2-(trifluoromethyl)benzylidene)-2-thioxothiazolidin-4-one (4) could effectively inhibit PRL-3 with IC50 value of 15.22 µM. Fluorescent assays suggested compound 4 tightly bound to tyrosine phosphatase PRL-3 with the molar ratio of 1:1, and the binding constant of 1.74 × 106 M-1. Compound 4 entered into SW-480 cells, selectively inhibited the expression of PRL-3 and increased the phosphorylation of PRL-3 substrates, and decreased the survival rate of SW-480 cells with IC50 of 6.64 µM and induced apoptosis. The results revealed that compound 4 is a dual functional inhibitor against the activity and expression of PRL-3 and a promising anti-cancer candidate targeting PRL-3.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Rodanina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Proteínas de Neoplasias/metabolismo , Proteínas Tirosina Fosfatases/metabolismo , Rodanina/síntese química , Rodanina/química , Relação Estrutura-Atividade
7.
J Am Vet Med Assoc ; 258(4): 395-406, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33539202

RESUMO

OBJECTIVE: To investigate disparities in hepatic copper concentrations determined by atomic absorption spectroscopy (AAS), inductively coupled plasma mass spectrometry (ICP-MS), and digital image analysis of rhodanine-stained sections. ANIMALS: 516 dogs. PROCEDURES: Medical records of dogs for which hepatic biopsy specimens had been submitted between January 1999 and December 2019 for evaluation of copper content were reviewed. Paired hepatic copper concentrations obtained with digital image analysis and AAS or ICP-MS were compared, and Spearman rank correlation coefficients were calculated to test for correlations between qualitative copper accumulation scores and hepatic copper concentrations. For dogs for which ≥ 4 rhodanine-stained hepatic sections were available, intraindividual variation in copper distribution across hepatic sections was evaluated. RESULTS: Median hepatic copper concentrations obtained with digital image analysis exceeded concentrations obtained with AAS or ICP-MS. Concentrations were also higher in older dogs (≥ 9 years vs < 9 years), dogs of breeds with a typical body weight ≥ 20 kg (44 lb), and dogs with necroinflammatory changes or uneven copper distribution. Qualitative copper accumulation scores were significantly associated with hepatic copper concentrations; however, the correlation between qualitative score and concentration obtained with digital image analysis (rs = 0.94) was higher than the correlation between qualitative score and concentration obtained with AAS (rs = 0.75) or ICP-MS (rs = 0.57). The coefficient of variation for hepatic copper concentrations obtained with digital image analysis was significantly higher for dogs with higher hepatic copper concentrations. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that spectroscopic-spectrometric analysis of hepatic biopsy specimens commonly underestimated the concentration obtained by digital image analysis of rhodanine-stained sections.


Assuntos
Cobre , Rodanina , Animais , Cães , Espectrometria de Massas/veterinária , Plasma , Análise Espectral/veterinária
8.
Chem Commun (Camb) ; 57(18): 2305-2308, 2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33533351

RESUMO

A two-pronged concept combining photodynamic therapy (PDT) and epithelial-mesenchymal transition (EMT) blockade in a minimalist nanoplatform was proposed to combat basal-like breast cancer (BLBC) metastasis. Based on PDT-mediated tumor killing and epalrestat (Epa)-mediated EMT blockade, as-prepared Ce6/Epa nanoparticles prevented BLBC metastasis effectively in vivo, providing a very promising two-pronged strategy against BLBC metastasis.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas/administração & dosagem , Fotoquimioterapia , Radiossensibilizantes/farmacologia , Rodanina/análogos & derivados , Tiazolidinas/farmacologia , Animais , Apoptose , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células , Clorofilídeos , Inibidores Enzimáticos/farmacologia , Transição Epitelial-Mesenquimal , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Camundongos , Camundongos SCID , Nanopartículas/química , Porfirinas/farmacologia , Rodanina/farmacologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
9.
J Mol Model ; 27(3): 75, 2021 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-33547544

RESUMO

Tuberculosis is the most dangerous disease causing maximum deaths than any other, caused by single infectious agent. Due to multidrug resistant of Mycobacterium tuberculosis strains, there is a need of new drugs and drug targets. In this work, we have selected RmlD (α-dTDP-6-deoxy-lyxo-4-hexulose reductase) in the dTDP Rhamnose pathway as drug target to control tuberculosis using Rhodanine analogues. In order to study interaction of RmlD with Rhodanine analogues, a three-dimensional model based on crystal structures such as 1VLO from Clostridium, 1KBZ from Salmonella typhimurium, and 2GGS from Sulfolobus was generated using Modeller 9v7. The modeled structure reliability has been checked using programs such as Procheck, What if, Prosa, Verify 3D, and Errat. In an attempt to find new inhibitors for RmlD enzyme, docking studies were done with a series of Rhodanine and its analogues. Detailed analysis of enzyme-inhibitor interactions identified specific key residues, SER5, VAL9, ILE51, HIS54, and GLY55 which were important in forming hydrogen bonds in binding affinity. Homology modeling and docking studies on RmlD model provided valuable insight information for designing better inhibitors as novel anti-tuberculosis drugs by rational method.


Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Mycobacterium tuberculosis/enzimologia , Rodanina/química , Rodanina/farmacologia , Sítios de Ligação , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Relação Estrutura-Atividade
10.
Bioorg Chem ; 106: 104483, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33268007

RESUMO

Two series of 5-aryl-furan derivatives bearing a phenylalanine- or isoleucine-derived rhodanine moiety were identified as competitive protein tyrosine phosphatase 1B (PTP1B) inhibitors. Among the compounds studied, 5g was found to have the best PTP1B inhibitory potency (IC50 = 2.66 ± 0.16 µM) and the best cell division cycle 25 homolog B (CDC25B) inhibitory potency (IC50 = 0.25 ± 0.02 µM). Enzymatic data together with molecular modeling results demonstrated that the introduction of a sec-butyl group at the 2-position of the carboxyl group remarkably improved the PTP1B inhibitory activity.


Assuntos
Inibidores Enzimáticos/farmacologia , Furanos/farmacologia , Isoleucina/farmacologia , Fenilalanina/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Rodanina/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Furanos/síntese química , Furanos/química , Humanos , Isoleucina/química , Estrutura Molecular , Fenilalanina/química , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Rodanina/química , Relação Estrutura-Atividade
11.
Mini Rev Med Chem ; 21(6): 738-789, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33334286

RESUMO

After the clinical use of epalrestat that contains a rhodanine ring, in type II diabetes mellitus and diabetic complications, rhodanin-based compounds have become an important class of heterocyclic in the field of medicinal chemistry. Various modifications to the rhodanine ring have led to a broad spectrum of biological activity of these compounds. Synthesis of rhodanine derivatives, depended on advenced throughput scanning hits, frequently causes potent and selective modulators of targeted enzymes or receptors, which apply their pharmacological activities through different mechanisms of action. Rhodanine-based compounds will likely stay a privileged scaffold in drug discovery because of different probability of chemical modifications of the rhodanine ring. We have, therefore reviewed their biological activities and structure activity relationship.


Assuntos
Química Farmacêutica , Rodanina/química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Farmacorresistência Bacteriana/efeitos dos fármacos , Humanos , Rodanina/farmacologia , Relação Estrutura-Atividade
12.
J Feline Med Surg ; 23(6): 526-533, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33026278

RESUMO

OBJECTIVES: The aim of this study was to assess hepatic copper concentrations and zonal distribution in cat liver specimens. METHODS: For this study, 121 archived, formalin-fixed, paraffin-embedded liver specimens from cats were used. Tissue sections were stained for copper with rhodanine and scored from 0 (no copper accumulation) to 5 (panlobular copper accumulation). The tissue specimens were then deparaffinized and hepatic copper concentrations were measured using flame atomic absorption spectroscopy. RESULTS: Tissue samples were categorized into four groups based on histopathologic findings: (1) no significant histopathologic hepatic changes (n = 66); (2) hepatic steatosis (n = 18); (3) inflammatory or infectious disease (n = 24); and (4) neoplasia (n = 13). Of the 121 specimens, 13 (11%) stained positive for copper, with three having a score ⩾3. Thirty-seven specimens (31%) had copper concentrations above the reference interval ([RI] <180 µg/g dry weight liver). Copper concentrations in cats with hepatic inflammatory or infectious disease were significantly higher than cats with hepatic steatosis (P = 0.03). Copper-staining score and concentration were positively correlated (rs = 0.46, P <0.001). CONCLUSIONS AND RELEVANCE: Despite the fact that 31% of specimens had copper concentrations above the RI, only 11% showed positive copper staining and only 2.5% had a score ⩾3. Our findings suggest that hepatic copper concentrations greater than the upper limit of the RI are relatively common in cats. Further studies to determine the factors that influence hepatic copper staining in cats and to establish contemporary RIs for hepatic copper in healthy cats are warranted.


Assuntos
Doenças do Gato , Fígado Gorduroso , Rodanina , Animais , Gatos , Cobre , Fígado Gorduroso/veterinária , Fígado
13.
Bioorg Chem ; 108: 104556, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33376013

RESUMO

Herein, a quantum mechanics/molecular mechanics (QM/MM) based biotransformation study was performed on synthetically feasible mutual-prodrugs of epalrestat which have been identified from an in-house database developed by us. These prodrugs were submitted to quantum polarized ligand docking (QPLD) with the CES1 enzyme followed by MM-GBSA calculation. Electronic aspects of transition state of these prodrugs were also considered to study the catalytic process through density functional theory (DFT). ADMET analysis of prodrugs was then carried out to assess the drug-likeness. On the basis of in-silico results, the best five prodrugs were synthesized and further evaluated for their neuroprotective and nephroprotective potential in high-fat diet-streptozotocin (HFD-STZ) induced diabetes in rat model. Clinically relevant molecular manifestations of diabetic complications (DC) including aldose reductase (ALR2) activity and oxidative stress markers such as reduced glutathione (GSH), catalase (CAT), and thiobarbituric acid reactive substances (TBARS) were determined in blood plasma as well as tissues of the brain and kidneys. The histopathological examination of these organs was also carried out to see the improvement in structural deformities caused due to neuropathy and nephropathy. Finally, in-vivo pharmacokinetic study was performed for the best two prodrugs to assess the improvement in biopharmaceutical attributes of parent drugs. Overall, EP-G-MFA and EP-MFA have significantly reduced the hyperglycemia-induced ALR2 activity, levels of oxidative stress markers, and manifested about a two-fold increase in the biological half-life (T1/2) of parent drugs. The overall findings of this study suggest that methyl ferulate conjugated prodrugs of epalrestat may be considered as potential protective agents in diabetic neuropathy and nephropathy.


Assuntos
Teoria da Densidade Funcional , Diabetes Mellitus Experimental/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Hipoglicemiantes/farmacologia , Pró-Fármacos/farmacologia , Rodanina/análogos & derivados , Tiazolidinas/farmacologia , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/patologia , Neuropatias Diabéticas/induzido quimicamente , Neuropatias Diabéticas/patologia , Relação Dose-Resposta a Droga , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Masculino , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/química , Ratos , Ratos Wistar , Rodanina/síntese química , Rodanina/química , Rodanina/farmacologia , Estreptozocina , Relação Estrutura-Atividade , Tiazolidinas/síntese química , Tiazolidinas/química
14.
Int J Nanomedicine ; 16: 8353-8373, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35002232

RESUMO

Background: Epalrestat (EPL) is a carboxylic acid derivative with poor aqueous solubility and its pharmacokinetic features are not fully defined. Purpose: Current research aimed to fabricate inclusion complexation of EPL with SBE7 ß-CD (IC) and EPL/SBE7 ß-CD CS NPs (NP). Methods: EPL was complexed with SBE7 ß-CD using the co-precipitation method, and the prepared complex was fabricated into nanoparticles using the ionic gelation method. The prepared formulations were characterized for particle size analysis, surface morphology, and in vitro dissolution study. The % inhibition of EPL against α-glucosidase enzyme was also conducted to check the drug's antidiabetic activity. Finally, an in vivo pharmacokinetic investigation was carried out to determine the concentration of EPL in rabbit plasma of the prepared formulation. In vivo pharmacokinetic studies were conducted by giving a single dose of pure EPL, IC, and NP. Results: The size of NP was found to be 241.5 nm with PDI 0.363 and zeta potential of +31.8 mV. The surface of the prepared NP was non-porous, smooth and spherical when compared with pure EPL, SBE7 ß-CD and IC. The cumulative drug release (%) from IC and NP was 73% and 88%, respectively, as compared to pure drug (25%). The % inhibition results for in vitro α-glucosidase was reported to be 74.1% and the predicted binding energy for in silico molecular docking was calculated to be -6.6 kcal/mol. The calculated Cmax values for EPL, IC and NP were 4.75±3.64, 66.91±7.58 and 84.27±6.91 µg/mL, respectively. The elimination half-life of EPL was 4 h and reduced to 2 h for IC and NP. The AUC0-α for EPL, IC and NP were 191.5±164.63, 1054.23±161.77 and 1072.5±159.54 µg/mL*h, respectively. Conclusion: Taking these parameters into consideration it can be concluded that IC and NP have prospective applications for greatly improved delivery and regulatedt release of poorly water soluble drugs, potentially leading to increase therapeutic efficacy and fewer side effects.


Assuntos
Quitosana , Nanopartículas , Animais , Disponibilidade Biológica , Portadores de Fármacos , Simulação de Acoplamento Molecular , Tamanho da Partícula , Coelhos , Rodanina/análogos & derivados , Tiazolidinas
15.
Yakugaku Zasshi ; 140(11): 1381-1388, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-33132274

RESUMO

Epalrestat (EPS), approved in Japan, is currently the only aldose reductase inhibitor that is available for the treatment of diabetic neuropathy. Recently, we found that EPS at near-plasma concentration increases the intracellular levels of glutathione (GSH) in rat Schwann cells. GSH, the most abundant non-protein thiol antioxidant in cells, is important for protection against oxidative stress. Oxidative stress is associated with the development and progression of many pathological conditions, such as atherosclerosis, diabetes, and neurodegeneration. In this study, we tested the hypothesis that EPS enhances resistance to oxidative stress, by using rat Schwann cells. To determine whether EPS protects Schwann cells from oxidative stress, we performed experiments by using radical generators, drugs, and heavy metals as the source of oxidative stress. EPS reduced the cytotoxicity induced by 2,2-azobis-[2-(2-imidazolin-2-yl) propane] dihydrochloride, 6-hydroxydopamine, cisplatin, palmitate, cadmium chloride, and manganese (II) sulfate, indicating that EPS plays a role in protecting cells from oxidative stress. We suggest that EPS has the potential to prevent the development and progression of disorders caused by oxidative stress.


Assuntos
Antioxidantes/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Glutationa/metabolismo , Metais Pesados/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Rodanina/análogos & derivados , Células de Schwann/metabolismo , Tiazolidinas/farmacologia , Aldeído Redutase/antagonistas & inibidores , Animais , Células Cultivadas , Inibidores Enzimáticos , Ratos , Rodanina/farmacologia
16.
Chem Biol Interact ; 332: 109286, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33038328

RESUMO

(4-Oxo-2-thioxothiazolidin-3-yl)acetic acids exhibit a wide range of pharmacological activities. Among them, the only derivative used in clinical practice is the aldose reductase inhibitor epalrestat. Structurally related compounds, [(5Z)-(5-arylalkylidene-4-oxo-2-thioxo-1,3-thiazolidin-3-yl)]acetic acid derivatives were prepared previously as potential antifungal agents. This study was aimed at the determination of aldose reductase inhibitory action of the compounds in comparison with epalrestat and evaluation of structure-activity relationships (SAR). The aldose reductase (ALR2) enzyme was isolated from the rat eye lenses, while aldehyde reductase (ALR1) was obtained from the kidneys. The compounds studied were found to be potent inhibitors of ALR2 with submicromolar IC50 values. (Z)-2-(5-(1-(5-butylpyrazin-2-yl)ethylidene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (3) was identified as the most efficacious inhibitor (over five times more potent than epalrestat) with mixed-type inhibition. All the compounds also exhibited low antiproliferative (cytotoxic) activity to the HepG2 cell line. Molecular docking simulations of 3 into the binding site of the aldose reductase enzyme identified His110, Trp111, Tyr48, and Leu300 as the crucial interaction counterparts responsible for the high-affinity binding. The selectivity factor for 3 in relation to the structurally related ALR1 was comparable to that for epalrestat. SAR conclusions suggest possible modifications to improve further inhibition efficacy, selectivity, and biological availability in the group of rhodanine carboxylic acids.


Assuntos
Ácido Acético/farmacologia , Aldeído Redutase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Ácido Acético/síntese química , Ácido Acético/química , Aldeído Redutase/metabolismo , Animais , Sítios de Ligação , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Células Hep G2 , Humanos , Cristalino/efeitos dos fármacos , Cristalino/enzimologia , Ligantes , Masculino , Ratos Wistar , Rodanina/análogos & derivados , Rodanina/química , Rodanina/farmacologia , Tiazolidinas/química , Tiazolidinas/farmacologia
17.
Virus Res ; 289: 198167, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32956749

RESUMO

Transmissible gastroenteritis virus (TGEV) and porcine deltacoronavirus (PDCoV) are members of the family coronaviridae and mainly cause acute diarrhea/vomiting, dehydration and mortality in piglets, which lead to huge economic losses to the swine industry. Rhodanine derivative LJ001 has been verified to be effective against some enveloped virus infections in vitro. In this study, we evaluated the antiviral activity of LJ001 towards TGEV and PDCoV replication on swine testicular(ST) cells. Our results showed the 50 % cellular cytotoxicity (CC50) value of LJ001 was 146.4 µM on ST cell. The virus titers of TGEV and PDCoV were obviously decreased in the presence of LJ001 with the concentrations of 3.125 and 12.5 µM, and LJ001 potently inhibited TGEV and PDCoV infection at the replication stages of viral life cycle. Further study indicated that LJ001 inhibited TGEV and PDCoV replication by inhibition of viral RNA and protein synthesis, and reducing virus yields at 12 and 24 h post-inoculation. These data indicated that LJ001 had antiviral activities on TGEV and PDCoV replications in vitro, which may serve as a new candidate for treatment of coronaviruses infections.


Assuntos
Infecções por Coronavirus , Deltacoronavirus/efeitos dos fármacos , Gastroenterite Suína Transmissível/tratamento farmacológico , Rodanina/farmacologia , Doenças dos Suínos/tratamento farmacológico , Vírus da Gastroenterite Transmissível/efeitos dos fármacos , Animais , Linhagem Celular , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/veterinária , Suínos
18.
Mol Biol Rep ; 47(8): 6091-6103, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32761301

RESUMO

Cervical cancer is the leading cause of cancer-related death among women worldwide. Identifying an effective treatment with fewer side effects is imperative, because all of the current treatments have unique disadvantages. Aldo-keto reductase family 1 member B1 (AKR1B1) is highly expressed in various cancers and is associated with tumor development, but has not been studied in cervical cancer. In the current study, we used CRISPR/Cas9 technology to establish a stable HeLa cell line with AKR1B1 knockout. In vitro, AKR1B1 knockout inhibited the proliferation, migration and invasion of HeLa cells, providing evidence that AKR1B1 is an innovative therapeutic target. Notably, the clinically used epalrestat, an inhibitor of aldose reductases, including AKR1B1, had the same effect as AKR1B1 knockout on HeLa cells. This result suggests that epalrestat could be used in the clinical treatment of cervical cancer, a prospect that undoubtedly requires further research. Moreover, aiming to determine the underlying regulatory mechanism of AKR1B1, we screened a series of differentially regulated genes (DEGs) by RNA sequencing and verified selected DEGs by quantitative RT-PCR. In addition, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of the DEGs revealed a correlation between AKR1B1 and cancer. In summary, epalrestat inhibits the progression of cervical cancer by inhibiting AKR1B1, and thus may be a new drug for the clinical treatment of cervical cancer.


Assuntos
Aldeído Redutase/fisiologia , Inibidores Enzimáticos/farmacologia , Proteínas de Neoplasias/fisiologia , Rodanina/análogos & derivados , Tiazolidinas/farmacologia , Neoplasias do Colo do Útero/tratamento farmacológico , Aldeído Redutase/antagonistas & inibidores , Aldeído Redutase/genética , Divisão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Ontologia Genética , Células HeLa , Humanos , Invasividade Neoplásica , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , RNA Guia/genética , RNA Guia/farmacologia , Rodanina/farmacologia , Ensaio Tumoral de Célula-Tronco , Neoplasias do Colo do Útero/patologia
19.
Int J Pharm ; 587: 119688, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32717281

RESUMO

Currently to treat diabetic eye diseases like cataract or diabetic retinopathy oral or intravitreal route is used, and there is still a demand for the efficient dosage forms. Contact lens can be used to deliver drug to the ocular tissues, however, the presence of hydrophobic drug like epalrestat alter the critical lens properties. In this study, Pluronic® F68 stabilized pegylated solid lipid nanoparticles laden contact lens was designed to deliver epalrestat to the anterior and posterior side of the eye without affecting the critical lens properties. The characterization studies indicate that the pegylated-solid lipid nanoparticles (p-SLNs) were more spherical and smaller in size in comparison to the non-pegylated-SLNs. The in vitro release studies suggest that the direct p-SLNs laden contact lenses (DL-EP-p-SLN) showed promising results (low burst release and sustain release up to 196 h) in comparison to the p-SLNs soaked contact lenses (SM-EP-p-SLN, high burst release and sustain release up to 144 h). The selected DL-EP-p-SLN-100 batch was found to be safe in ocular irritation study. In tear fluid (rabbit model) studies, the DL-EP-p-SLN-100 batch showed high epalrestat concentration at all-time points in comparison to the SM-EP-p-SLN-100 batch. The bio-distribution study indicate high epalrestat accumulation in the various ocular tissues including retina, which suggest the potential of p-SLNs laden contact lenses to deliver drug to the posterior side of the eye to treat diabetic eye conditions like cataract and diabetic retinopathy.


Assuntos
Lentes de Contato , Nanopartículas , Preparações Farmacêuticas , Animais , Sistemas de Liberação de Medicamentos , Lipídeos , Tamanho da Partícula , Poloxâmero , Coelhos , Retina , Rodanina/análogos & derivados , Tiazolidinas
20.
Int J Med Sci ; 17(9): 1246-1256, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32547320

RESUMO

Sorafenib is the standard systemic treatment for advanced hepatocellular carcinoma (HCC), and improving its therapeutic effects is crucial for addressing cancer aggression. We previously reported that epalrestat, an aldo-keto reductase 1B10 inhibitor, enhanced sorafenib's inhibitory effects on HCC xenograft in nude mice. This study aimed to elucidate the mechanism of epalrestat's anti-tumour enhancing effects on sorafenib. HepG2 cells were treated with sorafenib, epalrestat, and their combination. Cell proliferation was assessed with Cell Counting Kit-8 and colony formation assays. AKR1B10 supernate concentration and enzyme activity were detected by ELISA assay and the decrease of optical density of NADPH at 340 nm. Cell cycle and apoptosis analyses were performed with flow cytometry. Western blots clarified the molecular mechanism underlying effects on cell cycle, apoptosis, and autophagy. The anti-tumour mechanism was then validated in vivo through TUNEL and immunohistochemistry staining of HCC xenograft sections. Epalrestat combined with sorafenib inhibited HepG2 cellular proliferation in vitro, arrested the cell cycle at G0/G1, and promoted apoptosis and autophagy. Treatment with a specific mTOR activator MHY-1485 increased mTOR phosphorylation, while suppressing apoptosis and autophagy. Consistent with in vitro results, data from the HCC-xenograft nude mouse model also indicated that combined treatment inhibited the mTOR pathway and promoted apoptosis and autophagy. In conclusion, epalrestat heightens sorafenib's anti-cancer effects via blocking the mTOR pathway, thus inducing cell cycle arrest, apoptosis, and autophagy.


Assuntos
Membro B10 da Família 1 de alfa-Ceto Redutase/metabolismo , Rodanina/análogos & derivados , Sorafenibe/farmacologia , Tiazolidinas/farmacologia , Membro B10 da Família 1 de alfa-Ceto Redutase/genética , Protocolos de Quimioterapia Combinada Antineoplásica , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Western Blotting , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Imunofluorescência , Células Hep G2 , Xenoenxertos , Humanos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Rodanina/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo
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