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1.
J Agric Food Chem ; 67(37): 10521-10533, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31461284

RESUMO

This work was designed to comparatively investigate 27 dietary flavonoids that act as α-glucosidase inhibitors and insulin sensitizers. On the basis of the results of an in vitro experiment of α-glucosidase inhibition, myricetin (IC50 = 11.63 ± 0.36 µM) possessed the strongest inhibitory effect, followed by apigenin-7-O-glucoside (IC50 = 22.80 ± 0.24 µM) and fisetin (IC50 = 46.39 ± 0.34 µM). A three-dimensional quantitative structure-activity relationship model of α-glucosidase inhibitors with good predictive capability [comparative molecular field analysis, q2 = 0.529, optimum number of components (ONC) = 10, R2 = 0.996, F = 250.843, standard error of estimation (SEE) = 0.064, and two descriptors; comparative similarity index analysis, q2 = 0.515, ONC = 10, R2 = 0.997, F = 348.301, SEE = 0.054, and four descriptors] was established and indicated that meta positions of ring B favored bulky and minor, electron-withdrawing, and hydrogen bond donor groups. The presence of electron-donating and hydrogen bond acceptor groups at position 4' of ring B could improve α-glucosidase activity. Position 3 of ring C favored minor, electron-donating, and hydrogen bond donor groups, whereas position 7 of ring A favored bulky and hydrogen bond acceptor groups. Molecular docking screened five flavonoids (baicalein, isorhamnetin-3-O-rutinoside, apigenin-7-O-glucoside, kaempferol-7-O-ß-glucoside, and cyanidin-3-O-glucoside) that can act as insulin sensitizers and form strong combinations with four key protein targets involved in the insulin signaling pathway. Apigenin-7-O-glucoside (60 µM) can effectively improve insulin resistance, and glucose uptake increased by approximately 73.06% relative to the model group of insulin-resistant HepG2 cells. Therefore, apigenin-7-O-glucoside might serve as the most effective α-glucosidase inhibitor and insulin sensitizer. This work may guide diabetes patients to improve their condition through dietary therapy.


Assuntos
Flavonoides/química , Inibidores de Glicosídeo Hidrolases/química , Insulina/metabolismo , Flavonoides/metabolismo , Flavonoides/farmacologia , Inibidores de Glicosídeo Hidrolases/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Células Hep G2 , Humanos , Simulação de Acoplamento Molecular , Saccharomyces cerevisiae/enzimologia , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/metabolismo , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo
2.
Chem Biodivers ; 16(8): e1900183, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31361076

RESUMO

This work describes the study of the chemical composition and bioactivity of the essential oils (EOs) of the different organs (leaves, flowers, stems and roots) from Eruca vesicaria. According to the GC and GC/MS analysis, all the EOs were dominated by erucin (4-methylthiobutyl isothiocyanate) with a percentage ranging from 17.9 % (leaves) to 98.5 % (roots). The isolated EOs were evaluated for their antioxidant (DPPH, ABTS and ß-carotene/linoleic acid), antibacterial and inhibitory property against α-amylase and α-glucosidase. Most EOs exhibited an interesting α-glucosidase and α-amylase inhibitory potential. The roots essential oil was found to be the most active with IC50 values of 0.80±0.06 and 0.11±0.01 µg mL-1 , respectively. The essential oil of roots exhibited the highest antioxidant activity (DPPH, PI=92.76±0.01 %; ABTS, PI=78.87±0.19; and ß-carotene, PI=56.1±0.01 %). The isolated oils were also tested for their antibacterial activity against two Gram-positive and three Gram-negative bacteria. Moderate results have been noted by comparison with Gentamicin used as positive control.


Assuntos
Antioxidantes/química , Brassicaceae/metabolismo , Óleos Voláteis/química , Antibacterianos/química , Antibacterianos/farmacologia , Brassicaceae/química , Flores/química , Flores/metabolismo , Cromatografia Gasosa-Espectrometria de Massas , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Hipoglicemiantes/química , Óleos Voláteis/metabolismo , Óleos Voláteis/farmacologia , Folhas de Planta/química , Folhas de Planta/metabolismo , Raízes de Plantas/química , Raízes de Plantas/metabolismo , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo
3.
J Sci Food Agric ; 99(14): 6380-6391, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31283026

RESUMO

BACKGROUND: Prickly pears are potential candidates for the development of low-cost functional foods because they grow with low water requirements in arid regions of the world. They are sources of betalains and phenolic compounds, which have been reported to contribute to human health. The study of the biological activity of different varieties and of their isolated bioactive constitutes is fundamental in the design of functional foods. In this context, our objective is the assessment of the ability of Spanish and Mexican prickly-pear cultivars to inhibit enzymes related to type 2 diabetes and the inflammatory response, and the contribution of their bioactive compounds to their nutra-pharmaceutical potential. RESULTS: Prickly pear peels presented the highest antioxidant activity due to their high isorhamnetin glycoside content. Isorhamnetin glycosides showed significantly higher antioxidant and anti-inflammatory activity than aglycone, particularly isorhamnetin glucosyl-rhamnosyl-pentoside (IG2), which also reported antihyperglycemic activity. Morada, Vigor, and Sanguinos whole fruits exhibited moderate α-amylase inhibition and higher α-glucosidase inhibition, which is ideal for lowering glucose absorption in hyperglycemia management. Sanguinos peels presented the highest anti-inflammatory activity because of their high indicaxanthin content and isorhamnetin glycoside profile. CONCLUSIONS: In the design of prickly pear functional foods, technological processing should prioritize the retention or concentration of these bioactive compounds to preserve (or increase) their natural antioxidant, antihyperglycemic and anti-inflammatory activity. Peels of red and orange varieties should be further evaluated for antioxidant and anti-inflammatory purposes while whole fruits of red and purple varieties could be considered possible candidates for hyperglycemia management. © 2019 Society of Chemical Industry.


Assuntos
Anti-Inflamatórios/química , Diabetes Mellitus Tipo 2/enzimologia , Inibidores Enzimáticos/química , Hipoglicemiantes/química , Extratos Vegetais/química , Pyrus/química , Antioxidantes/química , Betalaínas/química , Diabetes Mellitus Tipo 2/metabolismo , Frutas/química , Inibidores de Glicosídeo Hidrolases/química , Humanos , Cinética , Fenóis/química , Pyrus/classificação , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/química , alfa-Amilases/metabolismo , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo
4.
Comput Biol Chem ; 82: 25-36, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31255972

RESUMO

The prevalence of diabetes mellitus has been incremented in the current century and the need for novel therapeutic compounds to treat this disease has been significantly increased. One of the most promising approaches is to inhibit intestinal alpha glucosidases. Based on our previous studies, four pyrimidine-fused heterocycles (PFH) were selected as they revealed satisfactory inhibitory action against mammalian α-glucosidase. The interaction of these compounds with both active domains of human maltase-glucoamylase (MGAM) and their effect on human Caco-2 cell line were investigated. The docking assessments suggested that binding properties of these ligands were almost similar to that of acarbose by establishing hydrogen bonds especially with Tyr1251 and Arg526 in both C-terminal and N-terminal MGAM, respectively. Also, these compounds indicated a stronger affinity for C-terminal of MGAM. L2 and L4 made tightly complexes with both terminals of MGAM which in turn revealed the importance of introducing pyrimidine scaffold and its hinge compartment. The results of molecular dynamics simulation analyses confirmed the docking data and showed deep penetration of L2 and L4 into the active site of MGAM. Based on cell cytotoxicity assessments, no significant cell death induction was observed. Hence, these functional MGAM inhibitors might be considered as new potential therapeutic compounds in treatment of diabetes and its complications.


Assuntos
Inibidores de Glicosídeo Hidrolases/farmacologia , Pirimidinonas/farmacologia , alfa-Glucosidases/metabolismo , Acarbose/química , Células CACO-2 , Domínio Catalítico , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/toxicidade , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Compostos Heterocíclicos com 3 Anéis/toxicidade , Humanos , Ligações de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Pirimidinonas/química , Pirimidinonas/toxicidade , alfa-Glucosidases/química
5.
Food Chem ; 299: 125102, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31279126

RESUMO

The chemical compositions and α-glucosidase inhibitory activities of anthocyanins extracted from blueberry, blackcurrant and blue honeysuckle fruits and their acid hydrolysates (anthocyanidins) were analysed. Those anthocyanins were glycosidic anthocyanins that converted to anthocyanidins during acid hydrolysis, leading to increases in their α-glucosidase inhibitory activities (expressed as IC50 values) from 0.232, 0.152 and 0.188 to 0.113 to 0.005 and 0.025 mg/mL. The potential inhibitory mechanism of these anthocyanidins was then investigated through inhibition kinetics, fluorescence quenching and docking simulations. The results showed the following: 1) all anthocyanidins were mixed-type inhibitors of α-glucosidase and they bind more tightly to free α-glucosidase as compared to the α-glucosidase-substrate complex; 2) anthocyanidin inhibition of α-glucosidase was a static procedure, presumably driven by hydrophobic associations and hydrogen bonding; and 3) all anthocyanidins were inserted into the active site of α-glucosidase and avoided the entrance of p-nitrophenyl-a-D-glucopyranoside. This study is valuable for anthocyanidins as potential α-glucosidase inhibitors.


Assuntos
Antocianinas/farmacologia , Mirtilos Azuis (Planta)/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Lonicera/química , Ribes/química , Antocianinas/análise , Antocianinas/química , Fluorescência , Frutas/química , Inibidores de Glicosídeo Hidrolases/química , Ligações de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Cinética , Simulação de Acoplamento Molecular , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo
6.
J Agric Food Chem ; 67(31): 8617-8625, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31293160

RESUMO

Inhibiting starch digestion can effectively control postprandial blood sugar level. In this study, the in vitro digestion differences among the mixtures of five polyphenols (i.e., procyanidins [PAs], catechin [CA], tannic acid [TA], rutin [RU], and quercetin [QU]) and starch were analyzed through an in vitro simulation test of starch digestion. The interaction characteristics of these five polyphenols with α-amylase and α-glucosidase were investigated in terms of the inhibition effect, dynamics, fluorescence quenching, and circular dichroism (CD). The results revealed that the rapidly digestible starch (RDS) contents decreased, while the resistant starch (RS) contents increased. All five polyphenols inhibited the α-amylase activity through the noncompetitive approach but inhibited the α-glucosidase activity through the competitive approach. Five polyphenols combined with α-amylase spontaneously by using the hydrophobic effect. The interaction of PAs and QU with α-glucosidase were recognized as van der Waals forces and H bonding, whereas CA and TA interacted with α-glucosidase through the hydrophobic effect. All five polyphenols can cause conformational changes in enzymes.


Assuntos
Extratos Vegetais/química , Polifenóis/química , Amido/química , Animais , Digestão , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Cinética , Modelos Biológicos , Extratos Vegetais/metabolismo , Polifenóis/metabolismo , Amido/metabolismo , Suínos , Leveduras/enzimologia , alfa-Amilases/química , alfa-Amilases/metabolismo , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo
7.
Food Chem ; 297: 124988, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31253285

RESUMO

Agaricus blazei, Auricularia fuscosuccinea and Pleurotus albidus mycelia were obtained in solid-state cultivation (SSC), using grains (brown rice, canjica corn and wheat) as raw material. Colonized grain flours were analysed for their nutritional, physical and physico-chemical characteristics and biological activity in vitro. Wheat flour with P. albidus showed higher values for protein (18.34 g/100 g), ergosterol (0.60 mg/g), mycelial biomass (183 mg/g) and total amino acids (58.34 mg/g). Corn flour with A. fuscosuccinea showed the highest total phenolic content (2.38 mg GAE/g), antioxidant activity in the 1,1-diphenyl-2-picrylhydrazyl (DPPH) (8.90 µmol TEAC/g) and 2,2'-Azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) (16.52 µmol TEAC/g) assay. Wheat flour with P. albidus were more effective at inhibiting of pancreatic lipase (74.5%) and of α-glucosidase (98.2%). In conclusion, grains colonized by macrofungi mycelia through SSC can enrich the nutritional value and the biological activity of the flours, which presents a potential for functional foods.


Assuntos
Agaricus/fisiologia , Farinha/análise , Valor Nutritivo , Pleurotus/fisiologia , Aminoácidos/química , Antioxidantes/química , Biomassa , Ergosterol/análise , Lipase/antagonistas & inibidores , Lipase/metabolismo , Oryza/metabolismo , Fenóis/análise , Triticum/metabolismo , Zea mays/metabolismo , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo
8.
J Sci Food Agric ; 99(13): 5881-5889, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31206698

RESUMO

BACKGROUND: The suppression of α-glucosidase activity to retard glucose absorption is an important therapy for type-2 diabetes. Corosolic acid (CRA) is a potential antidiabetic component in many plant-based foods and herbs. In this study, the interplay mechanism between α-glucosidase and corosolic acid was investigated by several methods, including three-dimensional fluorescence spectra, circular dichroism spectra, and molecular simulation. RESULTS: Corosolic acid significantly inhibited α-glucosidase reversibly in an uncompetitive manner and its IC50 value was 1.35 × 10-5 mol L-1 . A combination of CRA with myricetin exerted a weak synergy against α-glucosidase. The intrinsic fluorescence of α-glucosidase was quenched via a static quenching course and the binding constant was 3.47 × 103 L mol-1 at 298 K. The binding of CRA to α-glucosidase was mainly driven by hydrophobic forces and resulted in a partial extension of the protein polypeptide chain with a loss of α-helix content. The molecular simulation illustrated that CRA bound to the entrance part of the active center of α-glucosidase and interacted with the amino acid residues Ser157, Arg442, Phe303, Arg315, Tyr158, and Gln353, which could hinder the release of substrate and catalytic reaction product, eventually suppressing the catalytic activity of α-glucosidase. CONCLUSIONS: These results may suggest new insights into corosolic acid from food sources as a potential α-glucosidase inhibitor that could better control diabetes. © 2019 Society of Chemical Industry.


Assuntos
Inibidores Enzimáticos/química , Triterpenos/química , alfa-Glucosidases/química , Motivos de Aminoácidos , Sítios de Ligação , Dicroísmo Circular , Humanos , Hipoglicemiantes/química , Simulação de Acoplamento Molecular
9.
J Sci Food Agric ; 99(13): 6001-6010, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31225640

RESUMO

BACKGROUND: In this study, we aimed to evaluate the influence of different extraction procedures [decoction, homogenizer-assisted extraction (HAE), infusion, maceration, Soxhlet and ultrasound-assisted extraction (UAE)] on the chemical profiling and biological properties of methanol and water extracts of Pulicaria dysenterica (L.) Bernh. The chemical profiles of the extracts were evaluated by high-performance liquid chromatography coupled to electrospray ionization and time-of-flight mass spectrometry (HPLC-ESI-TOF-MS). The antioxidant properties and enzymes (lipase, α-amylase, α-glucosidase, tyrosinase and cholinesterases) inhibitory potential of the extracts were evaluated. RESULTS: The chemical profiles were dependent on the type of extraction methods as well as on the type of solvent. The methanolic extracts showed higher levels of total phenolic, flavonoid, and phenolic acid content, while the highest total flavonol content was observed in the HAE-water extract. Forty different compounds were identified from P. dysenterica. In relation to the potential in vitro anti-diabetic effects, the highest activity against the studied key enzymes was observed for the macerated extract (α-amylase: 0.58 ± 0.03 and α- glucosidase: 1.65 ± 0.03 mmol ACAE g-1 ). The HAE-methanol extract was the most potent inhibitor of cholisterases, whereas the highest activities against tyrosinase were observed for UAE-methanol extract, followed by macerated and Soxhlet. The inhibitory activity of the studied extracts against lipase were in the order: soxhlet > macerated> HAE-methanol > UAE-methanol. CONCLUSION: This study has established scientific baseline data on the therapeutic properties of P. dysentrica, thereby advocating the need for further investigations in an endeavour to develop novel pharmaceuticals from this plant. © 2019 Society of Chemical Industry.


Assuntos
Extratos Vegetais/química , Pulicaria/química , Antioxidantes/química , Antioxidantes/isolamento & purificação , Cromatografia Líquida de Alta Pressão , Flavonoides/química , Flavonoides/isolamento & purificação , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/química , Análise Multivariada , Fenóis/química , Fenóis/isolamento & purificação , Extratos Vegetais/isolamento & purificação , Espectrometria de Massas por Ionização por Electrospray , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/química , alfa-Glucosidases/química
10.
J Agric Food Chem ; 67(25): 7025-7039, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31240933

RESUMO

As a functional food, the unripe fruits of Rubus chingii Hu have been widely used in China for thousands of years. Twenty-five major ellagitannins (ETs) were identified from the unripe fruits, and a novel ellagitannin, chingiitannin A (1), together with four other known ETs (2-5) were isolated and identified by HPLC-QTOF-MS/MS and 2D-NMR. Chingiitannin A showed the highest α-glucosidase and α-amylase inhibitory activities (IC50 2.89 and 4.52 µM, respectively), which occurred in a reversible and noncompetitive manner. Static quenching was indicated in a fluorescence quenching assay. Molecular docking results revealed that chingiitannin A interacted with the enzymes mainly by hydrogen bonding and was bound in the allosteric site. Chingiitannin A was nontoxic, and it increased the glucose uptake in L6 myotubes. The results suggested that the unripe fruits of Rubus chingii Hu are rich sources of ETs, and chingiitannin A might be a good candidate for functional foods or antidiabetic drugs.


Assuntos
Inibidores de Glicosídeo Hidrolases/química , Taninos Hidrolisáveis/química , Hipoglicemiantes/química , Extratos Vegetais/química , Rubus/química , Animais , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Frutas/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Taninos Hidrolisáveis/farmacologia , Hipoglicemiantes/farmacologia , Cinética , Simulação de Acoplamento Molecular , Estrutura Molecular , Mioblastos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Ratos , Espectrometria de Massas em Tandem , alfa-Glucosidases/química
11.
J Agric Food Chem ; 67(24): 6765-6772, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31180676

RESUMO

One unusual resveratrol tetramer, paeonilactiflorol (1), and 14 known compounds (2-15) were isolated from peony seeds ( Paeonia lactiflora) under the guidance of bioassay. Paeonilactiflorol (1) was determined by extensive HRESIMS, UV, IR, 1D and 2D NMR spectroscopic analyses. Most of the stilbenes showed obvious inhibition on PTP1B and α-glucosidase, superior to the monoterpene glycosides. Especially, the stilbene tetramer (1) and trimer (8) exhibited high activity inhibiting both PTP1B with IC50 values of 27.23 and 27.81 µM and α-glucosidase with IC50 values of 13.57 and 14.39 µM. Two trans-dimers (4 and 5) also showed dipeptidyl peptidase-4 (DPPIV) inhibitory activity (55.35% and 61.26%, 500 µM) in addition to PTP1B and α-glucosidase. Enzyme kinetic study indicated that the types of inhibition on PTP1B were noncompetitive for 3 and 5 and mixed for 8 and 10. Quantitative analysis suggested that the stilbene trimers 8 (23.17 ± 0.36 mg/g) and 10 (15.24 ± 0.25 mg/g) were the main contents in peony seeds and should be responsible for the antidiabetic effects. This investigation supports the therapeutic potential of peony seeds in the treatment of diabetes with stilbenes as the active constituents.


Assuntos
Inibidores da Dipeptidil Peptidase IV/química , Inibidores de Glicosídeo Hidrolases/química , Hipoglicemiantes/química , Paeonia/química , Extratos Vegetais/química , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Estilbenos/química , Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/isolamento & purificação , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Hipoglicemiantes/isolamento & purificação , Estrutura Molecular , Extratos Vegetais/isolamento & purificação , Proteína Tirosina Fosfatase não Receptora Tipo 1/química , Sementes/química , Estilbenos/isolamento & purificação , alfa-Glucosidases/química
12.
Eur J Med Chem ; 177: 362-373, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158750

RESUMO

Inhibiting the decomposition of carbohydrates into glucose or promoting glucose conversion is considered to be an effective treatment for type 2 diabetes. Herein, a series of novel xanthone-triazole derivatives were designed, synthesized, and their α-glucosidase inhibitory activities and glucose uptake in HepG2 cells were investigated. Most of the compounds showed better inhibitory activities than the parental compound a (1,3-dihydroxyxanthone, IC50 = 160.8 µM) and 1-deoxynojirimycin (positive control, IC50 = 59.5 µM) towards α-glucosidase. Compound 5e was the most potent inhibitor, with IC50 value of 2.06 µM. The kinetics of enzyme inhibition showed that compounds 5e, 5g, 5h, 6c, 6d, 6g and 6h were noncompetitive inhibitors, and molecular docking results were consistent with the noncompetitive property that these compounds bind to allosteric sites away from the active site (Asp214, Glu276 and Asp349). On the other hand, the glucose uptake assays exhibited that compounds 5e, 6a, 6c and 7g displayed high activities in promoting the glucose uptake. The cytotoxicity assays showed that most compounds were low-toxic to human normal hepatocyte cell line (LO2). These novel xanthone triazole derivatives exhibited dual therapeutic effects of α-glucosidase inhibition and glucose uptake promotion, thus they could be use as antidiabetic agents for developing novel drugs against type 2 diabetes.


Assuntos
Glucose/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Hipoglicemiantes/farmacologia , Triazóis/farmacologia , Xantonas/farmacologia , Sítios de Ligação , Desenho de Drogas , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/metabolismo , Inibidores de Glicosídeo Hidrolases/toxicidade , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/metabolismo , Hipoglicemiantes/toxicidade , Cinética , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/metabolismo , Triazóis/toxicidade , Xantonas/síntese química , Xantonas/metabolismo , Xantonas/toxicidade , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo
13.
Food Funct ; 10(5): 2881-2887, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31070208

RESUMO

Three dihydrochalcone-derived polyphenols, huperolides A-C (1-3), along with thirteen known compounds (4-16) were isolated from the leaves of Malus hupehensis, the well-known tea crab apple in China. Their chemical structures were elucidated by extensive spectroscopic analysis including NMR (HSQC, HMBC, 1H-1H COSY and ROESY), HRMS and CD spectra. Huperolide A is a polyphenol with a new type of carbon skeleton, while huperolides B and C are a couple of atropisomers, which were isolated from natural sources for the first time. The antihyperglycemic effects of the isolated compounds were evaluated based on assaying their inhibitory activities against α-glucosidase. As a result, phlorizin (4), 3-hydroxyphloridzin (5), 3-O-coumaroylquinic acid (12) and ß-hydroxypropiovanillone (15) showed significant concentration-dependent inhibitory effects on α-glucosidase. Therefore, those compounds might be responsible for the antihyperglycemic effect of this herb, and are the most promising compounds to lead discovery of drugs against diabetes.


Assuntos
Chalconas/química , Inibidores de Glicosídeo Hidrolases/química , Hipoglicemiantes/química , Malus/química , Extratos Vegetais/química , Folhas de Planta/química , Polifenóis/química , China , Humanos , Análise Espectral , alfa-Glucosidases/química
14.
Eur J Med Chem ; 176: 343-377, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31112894

RESUMO

α-Glucosidase enzyme inhibition is an effective therapeutic decorum in the treatment of type 2 diabetes mellitus. Since 1990, three α-glucosidase inhibitors are known to exist clinically, Acarbose, Voglibose and Miglitol. Side effects and long synthetic routes to access them forced the researchers to move their focus to discover simple and small heterocyclic motifs that work as promising α-glucosidase inhibitors and may eventually lead to the management of postprandial hyperglycemic condition in T2DM. In this regards, this review deals with recently discovered heterocyclic molecules that have been evaluated to exhibit inhibition of α-glucosidase enzyme.


Assuntos
Inibidores de Glicosídeo Hidrolases/química , Compostos Heterocíclicos/química , Animais , Linhagem Celular Tumoral , Inibidores de Glicosídeo Hidrolases/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/toxicidade , Compostos Heterocíclicos/metabolismo , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/toxicidade , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/metabolismo , Hipoglicemiantes/farmacologia , Hipoglicemiantes/toxicidade , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo
15.
Chem Biodivers ; 16(6): e1900032, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30957403

RESUMO

The inhibition of carbohydrate-hydrolyzing enzymes in human digestive organs is crucial in controlling blood sugar levels, which is important in treating type 2 diabetes. In the current study, pahangensin A (1), a bis-labdanic diterpene characterized previously in the rhizomes of Alpinia pahangensis Ridl., was identified as an active dual inhibitor for α-amylase (IC50 =114.80 µm) and α-glucosidase (IC50 =153.87 µm). This is the first report on the dual α-amylase and α-glucosidase inhibitory activities of a bis-labdanic diterpene. The Lineweaver-Burk plots of compound 1 indicate that it is a mixed-type inhibitor with regard to both enzymes. Based on molecular docking studies, compound 1 docked in a non-active site of both enzymes. The dual inhibitory activity of compound 1 makes it a suitable natural alternative in the treatment of type 2 diabetes.


Assuntos
Alpinia/química , Diterpenos/química , alfa-Amilases/metabolismo , alfa-Glucosidases/metabolismo , Alpinia/metabolismo , Sítios de Ligação , Domínio Catalítico , Diterpenos/isolamento & purificação , Diterpenos/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Cinética , Simulação de Acoplamento Molecular , Extratos Vegetais/química , alfa-Amilases/antagonistas & inibidores , alfa-Glucosidases/química
16.
Artigo em Inglês | MEDLINE | ID: mdl-30954797

RESUMO

α-Glucosidase (AG) is an important drug target for the treatment of type 2 diabetes mellitus in humans due to the potential effect of down regulating glucose absorption in patients. In our previous study, salvianolic acid A (SAA) was found to exhibit potent AG inhibitory activity, whereas the interaction mechanism was still ambiguous. Herein, the interaction mechanism of SAA and AG was investigated by multi-spectroscopic methods along with molecular docking. As a result, it was found that SAA reversibly inhibited AG in a competitive manner with IC50 of 16.44 ±â€¯0.18 µM, and the inhibition belonged to a multi-phase kinetics process with a first-order reaction. The intrinsic fluorescence of AG could be strongly quenched by SAA through a static quenching mechanism. The negative Gibbs free energy change and positive values of enthalpy and entropy change revealed that the binding of SAA to AG was spontaneous and dominated mainly by hydrophobic interactions, and only a single binding site was determined for them. Analysis of synchronous fluorescence, ANS-binding fluorescence, circular dichroism and Fourier transform infrared spectra suggested that the binding of SAA to AG induced rearrangement and conformational changes of the enzyme. Besides, further molecular modelling validated that SAA could bind to the active domain and prevent the entrance of substrate, resulting in the inhibition of AG activity. These findings provide new insights into understanding the interaction mechanism of SAA on AG.


Assuntos
Ácidos Cafeicos/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Lactatos/farmacologia , alfa-Glucosidases/metabolismo , Ácidos Cafeicos/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/enzimologia , Inibidores de Glicosídeo Hidrolases/química , Humanos , Ligações de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Cinética , Lactatos/química , Simulação de Acoplamento Molecular , Ligação Proteica , Termodinâmica , alfa-Glucosidases/química
17.
Molecules ; 24(8)2019 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-30999646

RESUMO

A series of symmetrical salicylaldehyde-bishydrazine azo molecules, 5a-5h, have been synthesized, characterized by 1H-NMR and 13C-NMR, and evaluated for their in vitro α-glucosidase and α-amylase inhibitory activities. All the synthesized compounds efficiently inhibited both enzymes. Compound 5g was the most potent derivative in the series, and powerfully inhibited both α-glucosidase and α-amylase. The IC50 of 5g against α-glucosidase was 0.35917 ± 0.0189 µM (standard acarbose IC50 = 6.109 ± 0.329 µM), and the IC50 value of 5g against α-amylase was 0.4379 ± 0.0423 µM (standard acarbose IC50 = 33.178 ± 2.392 µM). The Lineweaver-Burk plot indicated that compound 5g is a competitive inhibitor of α-glucosidase. The binding interactions of the most active analogues were confirmed through molecular docking studies. Docking studies showed that 5g interacts with the residues Trp690, Asp548, Arg425, and Glu426, which form hydrogen bonds to 5g with distances of 2.05, 2.20, 2.10 and 2.18 Å, respectively. All compounds showed high mutagenic and tumorigenic behaviors, and only 5e showed irritant properties. In addition, all the derivatives showed good antioxidant activities. The pharmacokinetic evaluation also revealed promising results.


Assuntos
Inibidores de Glicosídeo Hidrolases , Simulação de Acoplamento Molecular , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/química , alfa-Glucosidases/química , Animais , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , Estrutura Molecular , Suínos
18.
Chem Biodivers ; 16(5): e1900137, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30957408

RESUMO

A pair of new glycosidic epimers, cablinosides A (1a) and B (1b) were isolated from the leaves of Pogostemon cablin. The structures with absolute configurations of 1a and 1b were elucidated by extensive NMR investigation, and quantum chemical CD calculations. The epimer mixture 1 showed moderate α-glucosidase inhibitory activity and no significant cytotoxic activity against HepG2 cells.


Assuntos
Glicosídeos/química , Fenilacetatos/química , Pogostemon/química , Sobrevivência Celular/efeitos dos fármacos , Dicroísmo Circular , Glicosídeos/isolamento & purificação , Glicosídeos/farmacologia , Células Hep G2 , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Conformação Molecular , Fenilacetatos/isolamento & purificação , Fenilacetatos/farmacologia , Folhas de Planta/química , Folhas de Planta/metabolismo , Pogostemon/metabolismo , Estereoisomerismo , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo
19.
Molecules ; 24(7)2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-30987350

RESUMO

An efficient and practical method for the synthesis of 2,6-diaryl-4-oxo-N,N'-di(pyridin-2-yl)cyclohexane-1,1-dicarboxamide is described in this present study, which occurs through a double Michael addition reaction between diamide and various dibenzalacetones. The reaction was carried out in dichloromethane (DCM) in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The anticancer activities of the synthesized compounds were evaluated in several cancer cell lines, including MCF-7, MDA-MB-231, SAS, PC-3, HCT-116, HuH-7 and HepG2 cells. From these experiments, we determined that MDA-MB-231 was the most sensitive cancer cell line to the compounds 3c, 3e, 3d, 3j and 3l, which exhibited variable anticancer activities (3l [IC50 = 5 ± 0.25 µM] > 3e [IC50 = 5 ± 0.5 µM] > 3c [IC50 = 7 ± 1.12 µM] > 3d [IC50 = 18 ± 0.87 µM] > 3j [IC50 = 45 ± 3 µM]). Of these, 3l (substituted p-trifluoromethylphenyl and chloropyridine) showed good potency (IC50 = 6 ± 0.78 µM) against HCT-116 colorectal cancer cells and exhibited high toxicity against HuH-7 liver cancer cells (IC50 = 4.5 ± 0.3 µM). These values were three times higher than the values reported for cisplatin (IC50 of 8 ± 0.76 and 14.7 ± 0.5 µM against HCT-116 and HuH-7 cells, respectively). The highest α-glucosidase inhibitory activity was detected for the 3d, 3i and 3j compounds. The details of the binding mode of the active compounds were clarified by molecular docking studies.


Assuntos
Amidas/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Cicloexanonas/química , Cicloexanonas/farmacologia , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Piridinas/química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cicloexanonas/síntese química , Inibidores de Glicosídeo Hidrolases/síntese química , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Relação Estrutura-Atividade , alfa-Glucosidases/química
20.
Molecules ; 24(8)2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30991766

RESUMO

The edible and medicinal perennial herb dandelion is known to have antitumor, antioxidant, and anticomplement properties. However, the structural characterization and biological effects of its polysaccharides are not well understood. Here, we aimed to extract and investigate a novel polysaccharide from dandelion. A water-soluble polysaccharide, PD1-1, was successfully obtained from dandelion through ultrasonic-assisted extraction and purification using diethylaminoethyl (DEAE)-Sepharose fast flow and Sephadex G-75 columns. The results showed that PD1-1 is an inulin-type polysaccharide with a molecular weight of 2.6 kDa and is composed of glucose (52.39%), and mannose (45.41%). Glycosidic linkage analysis demonstrated that PD1-1 contains terminal α-d-Man/Glcp-(1→ and →1)-ß-d-Man/Glcf-(2→ glycosidic linkage conformations. A physicochemical analysis indicated that PD1-1 has a triple helix structure and exhibits important properties, including good swelling, water-holding, and oil-holding capacities. Furthermore, PD1-1 showed good antioxidant activities in DPPH and hydroxyl free radical scavenging abilities, with IC50 values of 0.23 mg/mL and 0.25 mg/mL, respectively, and good hypoglycemic activities in α-amylase and α-glucosidase inhibition, with IC50 values of 0.53 mg/mL and 0.40 mg/mL, respectively, in a concentration-dependent manner. Results suggest that PD1-1 possesses efficacious antioxidant and hypoglycemic properties and has potential applications as a functional food ingredient.


Assuntos
Antioxidantes/química , Inibidores de Glicosídeo Hidrolases/química , Polissacarídeos/química , Taraxacum/química , alfa-Amilases , alfa-Glucosidases/química , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/química
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