RESUMO
α-Glycosidase inhibition is one of the main approaches to treat Diabetes mellitus. Polyphenolic moieties are known to be responsible for yielding exhibit potent α-glycosidase inhibitory effects. In addition, compounds containing benzothiazole and Schiff base functionalities were previously reported to show α-glycosidase inhibition. In this paper, the synthesis of seven new phloroglucinol-containing benzothiazole Schiff base derivatives through the reaction of 6-substituted-2-aminobenzothiazole compounds with 2,4,6-trihydroxybenzaldehyde using acetic acid as a catalyst was reported. The synthesized compounds were characterized using spectroscopic methods such as FT-IR, 1H NMR, 13C NMR, and elemental analysis. The synthesized compounds were evaluated for their inhibitory effects on α-glycosidase, compounds 3f and 3g were found to show significant inhibitory properties when compared to the positive control. The IC50 values of 3f and 3g were calculated as 24.05 ± 2.28 and 18.51 ± 1.19 µM, respectively. Kinetic studies revealed that compounds 3f and 3g exhibited uncompetitive mode of inhibition against α-glycosidase. Molecular modeling predicted druglikeness for the title compounds and underpinned the importance of phloroglucinol hydroxyls for interacting with the key residues of α-glycosidase.
Assuntos
Benzotiazóis , Inibidores Enzimáticos , Polifenóis , Benzotiazóis/química , Benzotiazóis/farmacologia , Benzotiazóis/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Polifenóis/química , Polifenóis/farmacologia , Polifenóis/síntese química , Relação Estrutura-Atividade , Estrutura Molecular , Glicosídeo Hidrolases/antagonistas & inibidores , Glicosídeo Hidrolases/metabolismo , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/síntese química , Simulação de Acoplamento Molecular , Humanos , Relação Dose-Resposta a Droga , alfa-Glucosidases/metabolismo , CinéticaRESUMO
The misfolding and aggregation of α-Syn play a pivotal role in connecting diverse pathological pathways in Parkinson's disease (PD). Preserving α-Syn proteostasis and functionality by inhibiting its aggregation or disaggregating existing aggregates using suitable inhibitors represents a promising strategy for PD prevention and treatment. In this study, a series of benzothiazole-polyphenol hybrids was designed and synthesized. Three identified compounds exhibited notable inhibitory activities against α-Syn aggregation in vitro, with IC50 values in the low micromolar range. These inhibitors demonstrated sustained inhibitory effects throughout the entire aggregation process, stabilizing α-Syn proteostasis conformation. Moreover, the compounds effectively disintegrated preformed α-Syn oligomers and fibers, potentially by binding to specific domains within the fibers, inducing fibril instability, collapse, and ultimately resulting in smaller-sized aggregates and monomers. These findings offer valuable insights into the therapeutic potential of polyphenol hybrids with 2-conjugated benzothiazole targeting α-Syn aggregation in the treatment of PD.
Assuntos
Benzotiazóis , Polifenóis , Agregados Proteicos , alfa-Sinucleína , Benzotiazóis/química , Benzotiazóis/farmacologia , Benzotiazóis/síntese química , alfa-Sinucleína/antagonistas & inibidores , alfa-Sinucleína/metabolismo , Polifenóis/química , Polifenóis/farmacologia , Polifenóis/síntese química , Humanos , Agregados Proteicos/efeitos dos fármacos , Estrutura Molecular , Relação Estrutura-Atividade , Relação Dose-Resposta a Droga , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismoRESUMO
Phenols are widespread in nature, being the major components of several plants and essential oils. Natural phenols' anti-microbial, anti-bacterial, anti-oxidant, pharmacological and nutritional properties are, nowadays, well established. Hence, given their peculiar biological role, numerous studies are currently ongoing to overcome their limitations, as well as to enhance their activity. In this review, the functionalization of selected natural phenols is critically examined, mainly highlighting their improved bioactivity after the proper chemical transformations. In particular, functionalization of the most abundant naturally occurring monophenols, diphenols, lipidic phenols, phenolic acids, polyphenols and curcumin derivatives is explored.
Assuntos
Fenóis/farmacologia , Curcumina/síntese química , Curcumina/química , Curcumina/farmacologia , Esterificação , Fenóis/síntese química , Fenóis/química , Polifenóis/síntese química , Polifenóis/química , Polifenóis/farmacologiaRESUMO
Polylactic acid (PLA) is a promising food packaging material with biocompatible, nontoxic and biodegradable. In order to reduce the deterioration of aquatic products caused by microorganisms, PLA coaxial nanofiber films with cinnamaldehyde (CMA), tea polyphenol (TP) and its composite as core materials were prepared by using coaxial electrospinning technology. Its microscopic morphology and structure were characterized separately, and its thermal stability, wettability and mechanical properties were determined. The antibacterial activity and antibacterial mechanism of nanofiber films were studied with Shewanella putrefaciens (S. putrefaciens) which is the dominant spoilage of aquatic products as the target of action. The results show that the CMA/TP (m/m = 2:5)-PLA coaxial nanofibers have small diameter, uniform distribution, smooth surface, no pores and fracture. At the same time, the film has strong hydrophobicity, good thermal stability and mechanical properties. Its antibacterial performance is better than that of single-core nanofiber films, which effectively destroys the cell membrane of S. putrefaciens, increases the permeability of cell membrane, and interferes with the synthesis and expression of its protein. The coaxial nanofiber films with CMA, TP and its composite as core material can be used as a fresh-keeping material with antibacterial properties, and has potential application value in the field of food preservation.
Assuntos
Acroleína/análogos & derivados , Antibacterianos/síntese química , Poliésteres/química , Polifenóis/síntese química , Shewanella putrefaciens/efeitos dos fármacos , Chá/química , Acroleína/química , Antibacterianos/química , Antibacterianos/farmacologia , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Estabilidade de Medicamentos , Microbiologia de Alimentos , Embalagem de Alimentos , Temperatura Alta , Interações Hidrofóbicas e Hidrofílicas , Nanofibras , Polifenóis/química , Polifenóis/farmacologiaRESUMO
Resveratrol and quercetin are among the most studied plant polyphenols, and have many health-promoting actions. Strategies to accumulate them into mitochondria may be of therapeutic relevance, since these compounds are redox active and are well known to impact mitochondria and mitochondrial proteins. We report here the procedures to synthesize mitochondria-targeted resveratrol and quercetin derivatives; the synthetic strategies reported are however expected to be adaptable to other polyphenols with similar reactivity at the phenolic hydroxyls. Mitochondrial targeting can be achieved by conjugation with triphenylphosphonium , a lipophilic cation; this was linked via a butyl spacer forming an ether bond with one of the phenolic oxygens. The first step toward the synthesis of all mitochondriotropic derivatives described in this work is the production of a regiospecific -(4-O-chlorobutyl) derivative. Triphenylphosphonium (P+Ph3I-) is then introduced through two consecutive nucleophilic substitution steps: -Cl â -I â -P+Ph3I-. Pure mono-substituted chlorobutyl regioisomers are obtained by purification from the reaction mixture in the case of resveratrol , while specific protection strategies are required for quercetin to favor alkylation of one specific hydroxyl.Functionalization of the remaining hydroxyls can be exploited to modulate the physicochemical properties of the derivatives (i.e., water solubility, affinity for cell membranes); we report here synthetic protocols to obtain acetylated and methylated analogs.A brief description of some methods to assess the accumulation of the derivatives in mitochondria is also given; the proposed techniques are the use of a TPP +-selective electrode (with isolated rat liver mitochondria ) and fluorescence microscopy (with cultured cells).
Assuntos
Mitocôndrias Hepáticas/química , Polifenóis/síntese química , Quercetina/análogos & derivados , Resveratrol/análogos & derivados , Animais , Células HCT116 , Humanos , Mitocôndrias Hepáticas/efeitos dos fármacos , Estrutura Molecular , Compostos Organofosforados/química , Polifenóis/química , Polifenóis/farmacologia , RatosRESUMO
OBJECTIVE: This study aims to investigate the preparation of sustained-release microcapsules of salvianolic acid. METHODS: The stability of salvianolic acid microcapsules was improved, and the time of action was prolonged in the present study. This was prepared using the spray-drying method, with chitosan as the carrier. In the preparation process, the prescription and process were optimized by L9 (34) using an orthogonal design, with yield and drug loading as indexes, in order to obtain optimum conditions. RESULTS: The optimal process and prescription for the preparation of salvianolic acid microcapsules were found to be as follows: mass concentration of chitosan, 1.5%; mass ratio of salvianolic acid to chitosan, 1:3; inlet air temperature, 190°C; and peristaltic pump speed, 300 mL·h-1. The surface of the microcapsules was round, the drug loading was 25.99% ± 2.14%, the yield was 51.88% ± 2.84%, the entrapment efficiency was 86.21% ± 2.89%, and the average particle size was 105.6 ± 2.56 nm. The microcapsules in vitro had certain sustained release characteristics. The internally fitted first-order release model equation was ln(1-Q) = -0.236 t + 4.591 7, r = 0.920. In addition, the results of differential scanning calorimetry show that the properties of salvianolic acid were not changed by the microcapsules. CONCLUSION: Sustained-release microcapsules of salvianolic acid can be successfully prepared by adopting marine polysaccharide as a carrier.
Assuntos
Alcenos/química , Preparações de Ação Retardada/química , Polifenóis/química , Alcenos/síntese química , Cápsulas/síntese química , Cápsulas/química , Preparações de Ação Retardada/síntese química , Polifenóis/síntese químicaRESUMO
Black tea accounts for 70-80% of world tea production, and the polyphenols therein are produced by enzymatic oxidation of four tea catechins during tea fermentation. However, only limited groups of dimeric oxidation products, such as theaflavins, theasinensins, and theacitrins, have been isolated from black tea and chemically characterized. This is largely because of the complexity and heterogeneity of the oxidation products. To determine structures and production mechanisms of uncharacterized black tea polyphenols, in vitro model fermentation experiments using pure catechins and polyphenol oxidase have been applied, and basic oxidation mechanisms have been established. Contemporary methods, such as LC-MS, are also effective to identify catechin oxidation products in black tea. Despite ongoing efforts, almost 60% of the solids in black tea infusion remain uncharacterized. These compounds include the so-called thearubigins, which are a heterogeneous mixture of uncharacterized catechin oxidation products with oligomeric structures. This review summarizes the current knowledge of the production mechanisms of representative black tea polyphenols and presents recent progress in characterization of thearubigins.
Assuntos
Polifenóis/síntese química , Chá/química , Estrutura Molecular , Polifenóis/químicaRESUMO
The present study explores the methodology for the synthesis of bio-oil from waste trichosanthes cucumerina seeds by the solvent extraction method. It investigates the yield percentage, concentration of free fatty acids and acid contents in the extracted bio-oil. Effects of size of the crushed seeds, moisture content, extraction time, solvent to seed ratio and extraction temperatures were examined. The non-polar hexane solvent resulted in a higher percentage of oil yield (28.4 ± 0.4%) for the crushed seed size of 0.21 mm, 6% moisture content, 270 min extraction time, 68 °C temperature and 6:1(ml/g) of solvent to seed ratio. The synthesized bio-oil was characterized using Fourier Transform Infra-Red spectrum and Gas Chromatography-Mass Spectroscopy analysis. The properties of the bio-oil and biodiesel were assessed according to the American Society for Testing and Materials and the Association of Official Analytical Chemists standards. The obtained methyl-ester by trans-esterification process results in the fuel properties closer to the conventional fuel. Thus, Trichosanthes cucumerina bio-diesel can be used as a potential substitute.
Assuntos
Óleos de Plantas/síntese química , Polifenóis/síntese química , Energia Renovável , Trichosanthes/fisiologia , Biocombustíveis , Catálise , Esterificação , Cromatografia Gasosa-Espectrometria de Massas , Gasolina , Sementes , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
Despite the rapidly increasing number of patients suffering from type 2 diabetes, Alzheimer's disease, and diabetes-induced dementia, there are no disease-modifying therapies that are able to prevent or block disease progress. In this work, we investigate the potential of nature-inspired glucosylpolyphenols against relevant targets, including islet amyloid polypeptide, glucosidases, and cholinesterases. Moreover, with the premise of Fyn kinase as a paradigm-shifting target in Alzheimer's drug discovery, we explore glucosylpolyphenols as blockers of Aß-induced Fyn kinase activation while looking into downstream effects leading to Tau hyperphosphorylation. Several compounds inhibit Aß-induced Fyn kinase activation and decrease pTau levels at 10 µM concentration, particularly the per-O-methylated glucosylacetophloroglucinol and the 4-glucosylcatechol dibenzoate, the latter inhibiting also butyrylcholinesterase and ß-glucosidase. Both compounds are nontoxic with ideal pharmacokinetic properties for further development. This work ultimately highlights the multitarget nature, fine structural tuning capacity, and valuable therapeutic significance of glucosylpolyphenols in the context of these metabolic and neurodegenerative disorders.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/síntese química , Polifenóis/síntese química , Proteínas Proto-Oncogênicas c-fyn/antagonistas & inibidores , Proteínas tau/metabolismo , Doença de Alzheimer/metabolismo , Permeabilidade da Membrana Celular/efeitos dos fármacos , Colinesterases/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Descoberta de Drogas/métodos , Glucosídeos/química , Glucosídeos/farmacologia , Glicosídeo Hidrolases/antagonistas & inibidores , Células HEK293 , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Estrutura Molecular , Fosforilação , Polifenóis/química , Polifenóis/farmacologiaRESUMO
In recent years, phenolic compounds from plant sources, commonly referred to as 'plant polyphenols', have been the subject of an impressive number of research studies, to a large extent focused on the healthy properties attributed to diet polyphenols, including antioxidant, anti-inflammatory, antineoplastic, antidiabetic, neuroprotective, and other biological activities [...].
Assuntos
Anti-Inflamatórios , Antineoplásicos , Hipoglicemiantes , Fármacos Neuroprotetores , Plantas/química , Polifenóis , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/uso terapêutico , Polifenóis/síntese química , Polifenóis/química , Polifenóis/uso terapêuticoRESUMO
In order to improve the bioavailability of Juglans regia L. polyphenols (JRP) in human body, the novel Juglans regia L. polyphenols-Hohenbuehelia serotina polysaccharides (HSP) nanoparticles (JRP-HSP NPs) were synthesized based on electrostatic interaction. Moreover, the physicochemical properties, morphologies and gastrointestinal digestive characteristics of JRP-HSP NPs were respectively measured and analyzed. Among four kinds of JRP-HSP NPs prepared by different condition of mass ratio, JRP-HSP NPs (1:16) with encapsulation efficiency of 51.62%, average particle size of 341.0â¯nm, and zeta potential of -29.3 mv, presented better physicochemical properties, such as thermal stability, photostability and crystalline properties. Morphological analysis revealed JRP-HSP NPs (1:16) appeared spherical and almost uniform. Through evaluation of simulated gastrointestinal digestion, JRP-HSP NPs prevented the variation of phenolic composition induced by gastrointestinal digestion, which was similar as the one of undigested JRP, while un-encapsulated JRP exhibited totally different state due to degradation and biotransformation, suggesting that JRP-HSP NPs possessed the sustained release characteristics in gastrointestinal system. This study provided a non-toxic strategy to encapsulate polyphenols for improving their bioavailability.
Assuntos
Agaricales/química , Polissacarídeos Fúngicos/química , Juglans/química , Nanopartículas/química , Polifenóis/química , Polifenóis/farmacocinética , Disponibilidade Biológica , Digestão , Suco Gástrico/metabolismo , Humanos , Tamanho da Partícula , Polifenóis/síntese química , Saliva , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios XRESUMO
Stable σ-adducts of azolo[5,1-c]triazines and azolo[1,5-a]pyrimidines with different polyphenols were synthesized and their antioxidant and antiviral activity were investigated. Their affinity to viral hemagglutinin was assessed using molecular modelling. The phloroglucinol-modified azolo-azines possessed the highest virus-inhibiting activity. According to the results of the study of antioxidant properties of compounds, the most promising ones exhibiting highest antioxidant capacity were adducts containing in their structure pyrogallol and catechol residues and 6-nitro-triazolotriazin-7-ol scaffold. No correlation between antioxidant and virus-inhibiting activity of compounds studied was detected. The most active compounds demonstrated the ability to prevent binding of viral hemagglutinin with cellular receptor as shown in hemagglutination inhibition assay. Our results demonstrate that polyphenol-modified azolo-azines are prospective for further optimization as potential antivirals and that their action is directed against viral hemagglutinin.
Assuntos
Antioxidantes/farmacologia , Antivirais/farmacologia , Polifenóis/farmacologia , Triazinas/farmacologia , Triazóis/farmacologia , Animais , Antioxidantes/síntese química , Antioxidantes/metabolismo , Antivirais/síntese química , Antivirais/metabolismo , Cães , Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Vírus da Influenza A/efeitos dos fármacos , Células Madin Darby de Rim Canino , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Polifenóis/síntese química , Polifenóis/metabolismo , Ligação Proteica , Triazinas/síntese química , Triazinas/metabolismo , Triazóis/síntese química , Triazóis/metabolismoRESUMO
Twenty-one natural and unnatural phenolic compounds containing a carbohydrate moiety were synthesized and their structure-activity relationship (SAR) was evaluated for α-glucosidase inhibition and antioxidative activity. Varying the position of the galloyl unit on the 1,5-anhydro-d-glucitol (1,5-AG) core resulted in changes in the α-glucosidase inhibitory activity and notably, particularly strong activity was demonstrated when the galloyl unit was present at the C-2 position. Furthermore, increasing the number of the galloyl units significantly affected the α-glucosidase inhibition, and 2,3,4,6-tetra-galloyl-1,5-AG (54) and 2,3,4,6-tetra-galloyl-d-glucopyranose (61) exhibited excellent activities, which were more than 13-fold higher than the α-glucosidase inhibitory activity of acertannin (37). Moreover, a comparative structure-activity study suggested that a hemiacetal hydroxyl functionality in the carbohydrate core and a biaryl bond of the 4,6-O-hexahydroxydiphenoyl (HHDP) group, which are components of ellagitannins including tellimagrandin I, are not necessary for the α-glucosidase inhibitory activity. Lastly, the antioxidant activity increased proportionally with the number of galloyl units.
Assuntos
Antioxidantes/química , Inibidores de Glicosídeo Hidrolases/química , Polifenóis/química , alfa-Glucosidases , Antioxidantes/síntese química , Antioxidantes/farmacologia , Carboidratos/química , Desoxiglucose/química , Ácido Gálico/análogos & derivados , Ácido Gálico/síntese química , Ácido Gálico/química , Glucosídeos/síntese química , Glucosídeos/química , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/farmacologia , Estrutura Molecular , Extratos Vegetais/química , Polifenóis/síntese química , Polifenóis/farmacologia , Relação Estrutura-Atividade , alfa-Glucosidases/químicaRESUMO
In this work, we proved the efficient synthesis of a bio-based hyper-branched polyphenol from a modified lignin degradation fragment. Protocatechuic acid was readily obtained from vanillin, a lignin degradation product, via alkaline conditions, and further polymerised to yield high molecular weight hyperbranched phenol terminated polyesters. Vanillic acid was also subjected to similar polymerisation conditions in order to compare polymerisation kinetics and differences between linear and hyperbranched polymers. Overall, protocatechuic acid was faster to polymerise and more thermostable with a degradation temperature well above linear vanillic acid polyester. Both polymers exhibited important radical scavenging activity (RSA) compared to commercial antioxidant and present tremendous potential for antioxidant applications.
Assuntos
Técnicas de Química Sintética , Lignina/química , Fenol/química , Polímeros/química , Antioxidantes/síntese química , Antioxidantes/química , Fenol/síntese química , Polimerização , Polímeros/síntese química , Polifenóis/síntese química , Polifenóis/química , Termodinâmica , TermogravimetriaRESUMO
While plant polyphenols possess a variety of biological properties, exploration of chemical diversity around them is still problematic. Here, an example of application of the Ugi multicomponent reaction to the combinatorial assembly of artificial, yet "natural-like", polyphenols is presented. The synthesized compounds represent a second-generation library directed to the inhibition of ß-amyloid protein aggregation. Chiral enantiopure compounds, and polyphenol-ß-lactam hybrids have been prepared too. The biochemical assays have highlighted the importance of the key pharmacophores in these compounds. A lead for inhibition of aggregation of truncated protein AßpE3-42 was selected.
Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/química , Polifenóis/química , Polifenóis/farmacologia , Doença de Alzheimer , Fenômenos Químicos , Técnicas de Química Sintética , Humanos , Estrutura Molecular , Polifenóis/síntese química , Agregados Proteicos/efeitos dos fármacos , Análise EspectralRESUMO
Ellagitannin-derived ellagic acid (EA) and colonic metabolite urolithins are functional dietary ingredients for cancer prevention, but the underlying mechanism need elucidation. Mucin-type O-glycosylation, initiated by polypeptide N-acetyl-α-galactosaminyltransferases (ppGalNAc-Ts), fine-tunes multiple biological processes and is closely associated with cancer progression. Herein, we aim to explore how specific tannin-based polyphenols affect tumor behavior of colorectal cancer cells (CRC) by modulating O-glycosylation. Utilizing HPLC-based enzyme assay, we find urolithin D (UroD), EA and gallic acid (GA) potently inhibit ppGalNAc-Ts. In particular, UroD inhibits ppGalNAc-T2 through a peptide/protein-competitive manner with nanomolar affinity. Computational simulations combined with site-directed mutagenesis further support the inhibitors' mode of action. Moreover, lectin analysis and metabolic labelling reveal that UroD can reduce cell O-glycans but not N-glycans. Transwell experiments prove that UroD inhibits migration and invasion of CRC cells. Our work proves that specific tannin-based polyphenols can potently inhibit ppGalNAc-Ts activity to reduce cell O-glycosylation and lead to lowering the migration and invasion of CRC cells, suggesting that disturbance of mucin-type O-glycosylation is an important mechanism for the function of dietary polyphenols.
Assuntos
Carcinogênese/efeitos dos fármacos , Neoplasias Colorretais/prevenção & controle , N-Acetilgalactosaminiltransferases/antagonistas & inibidores , Peptídeos/antagonistas & inibidores , Polifenóis/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , N-Acetilgalactosaminiltransferases/metabolismo , Peptídeos/metabolismo , Polifenóis/síntese química , Polifenóis/química , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Several 4,6-diarylpyrimidin-2-amine derivatives show anticancer properties. However, their mode of action is not fully characterized. To develop potent anticancer chemotherapeutic agents, we designed and synthesized 25 4,6-diphenylpyrimidin-2-amine derivatives containing a guanidine moiety. METHODS: Clonogenic long-term survival assays were performed to screen anticancer compounds. To derive the structural conditions showing good cytotoxicities against cancer cells, quantitative structure-activity relationships (QSAR) were calculated. Biological activities were determined by flow cytometry for cell cycle analysis and by immunoblot analysis for the detection of Aurora kinase A (AURKA) activity. Because 2-(2-Amino-6-(2,4-dimethoxyphenyl)pyrimidin-4-yl) phenol (derivative 12) selectively inhibited AURKA activity from the kinome assay, in silico docking experiments were performed to elucidate the molecular binding mode between derivative 12 and AURKA. RESULTS: The pharmacophores were derived based on the QSAR calculations. Derivative 12 inhibited AURKA activity and reduced phosphorylation of AURKA at Thr283 in HCT116 human colon cancer cells. Derivative 12 caused the accumulation of the G2/M phase of the cell cycle and triggered the cleavages of caspase-3, caspase -7, and poly(ADP-ribose) polymerase. The binding energies of 30 apo-AURKA - derivative 12 complexes obtained from in silico docking ranged from -16.72 to -11.63 kcal/mol. CONCLUSIONS: Derivative 12 is an AURKA inhibitor, which reduces clonogenicity, arrests the cell cycle at the G2/M phase, and induces caspase-mediated apoptotic cell death in HCT116 human colon cancer cells. In silico docking demonstrated that derivative 12 binds to AURKA well. The structure-activity relationship calculations showed hydrophobic substituents and 1-naphthalenyl group at the R2 position increased the activity. The existence of an H-bond acceptor at C-2 of the R1 position increased the activity, too. Graphical abstract Derivative 12 inhibits Aurora kinase A activity and causes the G2/M phase arrest of the cell cycle.
Assuntos
Antineoplásicos/síntese química , Aurora Quinase A/antagonistas & inibidores , Polifenóis/síntese química , Pirimidinas/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Guanidina/química , Células HCT116 , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Polifenóis/química , Polifenóis/farmacologia , Relação Quantitativa Estrutura-AtividadeRESUMO
Xanthine oxidase (XO) has emerged as an important target for gout. In our previous study, salvianolic acid C (SAC) was found to show potent XO inhibitory activity, whereas the interaction mechanism was still not clear. Herein, an integrated approach consisting of enzyme kinetics, multi-spectroscopic methods and molecular docking was employed to investigate the interaction between SAC and XO. Consequently, SAC exhibited a rapid and mixed-type inhibition of XO with IC50 of 5.84⯱â¯0.18⯵M. The fluorescence data confirmed that SAC presented a strong fluorescence quenching effect through a static quenching procedure. The values of enthalpy change, entropy change and Gibbs free energy change indicated that their binding was spontaneous and driven mainly by hydrophobic interactions. Analysis of synchronous fluorescence, circular dichroism and fourier transform infrared spectra demonstrated that SAC induced conformational changes of the enzyme. Besides, further molecular docking revealed that SAC occupied the catalytic center resulting in the inhibition of XO activity. This study provides a comprehensive understanding on the interaction mechanism of SAC on XO.
Assuntos
Alcenos/farmacologia , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Polifenóis/farmacologia , Xantina Oxidase/antagonistas & inibidores , Alcenos/síntese química , Alcenos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Polifenóis/síntese química , Polifenóis/química , Espectrometria de Fluorescência , Relação Estrutura-Atividade , Xantina Oxidase/metabolismoRESUMO
Gliomas are lethal and aggressive form of brain tumors with resistance to conventional radiation and cytotoxic chemotherapies; inviting continuous efforts for drug discovery and drug delivery. Interestingly, small molecule hybrids are one such pharmacophore that continues to capture interest owing to their pluripotent medicinal effects. Accordingly, we earlier reported synthesis of potent Styryl-cinnamate hybrids (analogues of Salvianolic acid F) along with its plausible mode of action (MOA). We explored iTRAQ-LC/MS-MS technique to deduce differentially expressed landscape of native & phospho-proteins in treated glioma cells. Based on this, Protein-Protein Interactome (PPI) was looked into by employing computational tools and further validated in vitro. We hereby report that the Styryl-cinnamate hybrid, an analogue of natural Salvianolic acid F, alters key regulatory proteins involved in translation, cytoskeleton development, bioenergetics, DNA repair, angiogenesis and ubiquitination. Cell cycle analysis dictates arrest at G0/G1 stage along with reduced levels of cyclin D; involved in G1 progression. We discovered that Styryl-cinnamate hybrid targets glioma by intrinsically triggering metabolite-mediated stress. Various oncological circuits alleviated by the potential drug candidate strongly supports the role of such pharmacophores as anticancer drugs. Although, further analysis of SC hybrid in treating xenografts or solid tumors is yet to be explored but their candidature has gained huge impetus through this study. This study equips us better in understanding the shift in proteomic landscape after treating glioma cells with SC hybrid. It also allows us to elicit molecular targets of this potential drug before progressing to preclinical studies.
Assuntos
Alcenos/farmacologia , Cinamatos/farmacologia , Glioma/tratamento farmacológico , Polifenóis/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Alcenos/síntese química , Alcenos/química , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cinamatos/síntese química , Cinamatos/química , Química Computacional , Ciclina D/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/genética , Glioma/patologia , Xenoenxertos , Humanos , Camundongos , Proteínas de Neoplasias/genética , Polifenóis/síntese química , Polifenóis/química , Mapas de Interação de Proteínas/efeitos dos fármacos , Proteômica , Bibliotecas de Moléculas Pequenas/síntese químicaRESUMO
Antimicrobial resistance is widely recognized as a grave threat to global health in the 21st century, since the past decades have seen a dramatic increase in human-pathogenic bacteria that are resistant to one or multiple antibiotics. New antimicrobial agents are urgently required, particularly in the treatment of chronic infections such as cystic fibrosis, often associated with persistent colonization by drug-resistant pathogens and epithelial damage by pulmonary oxidative stress. In such events, it would be favourable to find agents that could have antioxidant and antibacterial activities combined in one molecule. The discovery of compounds that can show a dual-target activity considerably increased in the last years, reflecting the growing confidence that this new approach could lead to better therapeutic solutions for complex multigenic diseases. The aim of this review is to report those natural and synthetic compounds displaying significant antioxidant and antibacterial activities. In recent years there has been a growing attention on plant-derived antimicrobials as an alternative to antibiotics, for their efficacy and low tendency in developing bacterial resistance. Moreover, it was found that some natural products could enhance the activity of common antibiotics displaying a synergistic effect. We then report some selected synthetic compounds with an in-built capacity to act on two targets or with the combination in a single structure of two pharmacophores with antioxidant and antibacterial activities. Recent literature instances were screened and the most promising examples of dual-active antibacterial-antioxidant molecules were highlighted.