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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.
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
3.
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
4.
Chin J Nat Med ; 17(4): 303-307, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31076134

RESUMO

Four new octadecanoid derivatives (1-4) including a pair of enantiomers (1/2), along with 12 known analogues (5-16), were isolatedfrom the seeds of Ipomoea nil. Their structures were determined by detailed spectroscopic analyses and comparison with reported data of structurally related compounds, with the absolute configurations of 1 and 2 being assigned by an in situ dimolybdenum ECD method. Our bioassays revealed that these isolates did not show ABTS radical scavenging activity while 10 and 13 displayed better α-glucosidase inhibitory activity than the positive control acarbose (IC50 167.7 ± 1.55 µmol·L-1), with IC50 of 92.73 ± 3.12 and 11.39 ± 2.18µmol·L-1, respectively.


Assuntos
Ácidos Graxos/química , Inibidores de Glicosídeo Hidrolases/química , Ipomoea nil/química , Sementes/química , Ácidos Graxos/isolamento & purificação , Ácidos Graxos/metabolismo , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Inibidores de Glicosídeo Hidrolases/metabolismo , Concentração Inibidora 50 , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/metabolismo
5.
Mar Drugs ; 17(4)2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30974812

RESUMO

Chitosanase has attracted great attention due to its potential applications in medicine, agriculture, and nutraceuticals. In this study, P. mucilaginosus TKU032, a bacterial strain isolated from Taiwanese soil, exhibited the highest chitosanase activity (0.53 U/mL) on medium containing shrimp heads as the sole carbon and nitrogen (C/N) source. Using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis, a chitosanase isolated from P. mucilaginosus TKU032 cultured on shrimp head medium was determined at approximately 59 kDa. The characterized chitosanase showed interesting properties with optimal temperature and thermal stability up to 70 °C. Three chitosan oligosaccharide (COS) fractions were isolated from hydrolyzed colloidal chitosan that was catalyzed by TKU032 chitosanase. Of these, fraction I showed the highest α-glucosidase inhibitor (aGI) activity (65.86% at 20 mg/mL); its inhibitory mechanism followed the mixed noncompetitive inhibition model. Fractions II and III exhibited strong 2,2-diphenyl1-picrylhydrazyl (DPPH) radical scavenging activity (79.00% at 12 mg/mL and 73.29% at 16 mg/mL, respectively). In summary, the COS fractions obtained by hydrolyzing colloidal chitosan with TKU032 chitosanase may have potential use in medical or nutraceutical fields due to their aGI and antioxidant activities.


Assuntos
Proteínas de Bactérias/isolamento & purificação , Fatores Biológicos/biossíntese , Glicosídeo Hidrolases/isolamento & purificação , Oligossacarídeos/biossíntese , Paenibacillus/metabolismo , Animais , Proteínas de Bactérias/metabolismo , Biocatálise , Fatores Biológicos/farmacologia , Quitosana/metabolismo , Crustáceos/química , Ensaios Enzimáticos/métodos , Depuradores de Radicais Livres/metabolismo , Depuradores de Radicais Livres/farmacologia , Proteínas Fúngicas/metabolismo , Inibidores de Glicosídeo Hidrolases/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Glicosídeo Hidrolases/metabolismo , Temperatura Alta , Oligossacarídeos/farmacologia , Paenibacillus/isolamento & purificação , Estabilidade Proteica , Microbiologia do Solo , Especificidade por Substrato , alfa-Glucosidases/metabolismo
6.
BMC Complement Altern Med ; 19(1): 74, 2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30909900

RESUMO

BACKGROUND: Different plant parts of Roylea cinerea (D. Don) Baill. (Lamiaceae), Clematis grata Wall. (Ranunculaceae), Cornus capitata Wall. (Cornaceae) are traditionally used in the management of diabetes and various other diseases. METHOD: The air-dried plant parts from different plants were coarsely powdered and macerated in methanol to obtain their crude extracts. The crude extracts were evaluated for their α-glucosidase inhibitory activity. On the basis of results obtained, the methanolic crude extract of Cornus capitata Wall. was further sequentially fractionated in hexane, diethyl ether, ethyl acetate, n-butanol. Fractions obtained were also evaluated for their α-glucosidase inhibitory potential. The kinetic study was performed using Lineweaver Burk plot to evaluate the type of inhibition. Furthermore, in silico analysis was also carried with active sites of the enzyme (PDB ID: 3WY1) using Autodock4. RESULTS: Among all the plant extracts, Cornus capitata extract showed maximum inhibitory activity. Therefore its methanolic extract was further fractionated with the help of different solvents and the maximum activity was shown by the ethyl acetate fraction (IC50 50 µg/mL). Kinetic analysis indicated that Vmax and Km were increased indicating a competitive type of inhibition. In docking studies, among different constituents known in this plant, betulinic acid showed minimum binding energy (- 10.21 kcal/mol). The kinetic and docking studies have strengthened the observation made in the present study regarding the α-glucosidase inhibitory activity of Cornus capitata. CONCLUSION: The study provided partial evidence for pharmacological basis regarding clinical applications of Cornus capitata in the treatment of diabetes suggesting it to be a suitable candidate for the treatment of postprandial hyperglycemia.


Assuntos
Inibidores de Glicosídeo Hidrolases , Hipoglicemiantes , Extratos Vegetais , Plantas Medicinais/química , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/metabolismo , Hipoglicemiantes/farmacologia , Cinética , Metanol , Simulação de Acoplamento Molecular , Extratos Vegetais/química , Extratos Vegetais/metabolismo , Extratos Vegetais/farmacologia , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo
7.
Chem Asian J ; 14(9): 1409-1412, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-30859722

RESUMO

Purpose-designed 2-phenylquinoline (PQ)-sugar hybrids 1 and 2 were synthesized and evaluated for their photodegradation activities against an α-glucosidase target. The results indicated that PQ-mannose hybrid 2 selectively and effectively photodegraded α-glucosidase and significantly inhibited its enzymatic activity upon irradiation with long-wavelength UV light in the absence of any additives under neutral and aqueous conditions. Furthermore, 2 selectively and effectively inhibited α-glucosidase activity only with photo-irradiation even in complex cell lysate.


Assuntos
Inibidores de Glicosídeo Hidrolases/química , Monossacarídeos/química , Quinolinas/química , alfa-Glucosidases/metabolismo , 1-Desoxinojirimicina/química , Glucosamina/análogos & derivados , Glucosamina/química , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/metabolismo , Fotólise/efeitos da radiação , Raios Ultravioleta , alfa-Glucosidases/química
8.
Arch Microbiol ; 201(6): 737-746, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30820617

RESUMO

Marine actinobacteria are less explored than their terrestrial counterparts as potential source of natural products. The present study was aimed to elucidate the bioactive potential of metabolites produced by marine-derived actinobacterial strain Streptomyces sp.SCA29 isolated from Havelock Island, Andaman and Nicobar Islands, India. The potential isolate SCA29 was identified as Streptomyces sp. by phenotypic, genotypic (16S-rRNA) and phylogenetic analyses. The crude bioactive compound was extracted using organic solvents. The compounds were subjected to separation and purification by column chromatography which yielded six fractions. Each fraction was assayed for inhibition of α-glucosidase and α-amylase enzymes, antagonistic activity against bacterial pathogens, and cytotoxic activity against various cell lines. The fraction F3c was considered to be highly active owing to its significant inhibition potential against α-glucosidase and α-amylase enzymes with IC50 values as 44.26 and 53.19 µg/mL, respectively. The active fraction showed antibacterial activity against test bacterial pathogens with the MIC value ranged from 3.90 to 31.25 µg/mL. The compound also exhibited concentration-dependent cytotoxicity on various cell lines without significant effect against human normal cells. The bioassay-guided fractionation of extract led to the identification of 4-methoxyacetanilide, an acetamide derivative. The structure of the bioactive compound was confirmed by HR-MS, NMR (1H and 13C) and FT-IR spectra, and by comparison with literature data.


Assuntos
Acetanilidas/isolamento & purificação , Acetanilidas/farmacologia , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/farmacologia , Streptomyces/metabolismo , Acetanilidas/química , Acetanilidas/metabolismo , Antibacterianos/química , Antibacterianos/metabolismo , Linhagem Celular , DNA Bacteriano/genética , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Inibidores de Glicosídeo Hidrolases/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Humanos , Índia , Filogenia , RNA Ribossômico 16S/genética , Espectroscopia de Infravermelho com Transformada de Fourier , Streptomyces/classificação , Streptomyces/genética , Streptomyces/isolamento & purificação , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/química , alfa-Glucosidases/química
9.
Carbohydr Polym ; 209: 350-355, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30732817

RESUMO

This study investigated the in vitro and in silico inhibitory properties of fucoidan extracted from Turbinaria conoides against α-amylase and α-D-glucosidase. Extracted fucoidan contained 59 and 35% of fucose and sulphate and was characterized using 1H NMR. Dose dependent inhibition assays showed maximum of 85 and 72% of inhibition for α-amylase and α-D-glucosidase at 2.07 and 1.03 µM concentration of fucoidan. The IC50 value of fucoidan was found to be 1.07 and 0.68 µM against α-amylase and α-D-glucosidase. In silico studies (grid based docking) by Schrödinger software revealed that fucoidan as a potent inhibitor for both α-amylase and α-D-glucosidase based on number of interactions, hydrogen bond length and binding energy. Furthermore, fucoidan fulfilled the pharmacokinetic properties thus promising to develop fucoidan as drug for type 2 DM.


Assuntos
Simulação por Computador , Diabetes Mellitus Tipo 2/enzimologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Polissacarídeos/farmacologia , alfa-Amilases/antagonistas & inibidores , alfa-Glucosidases/metabolismo , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/metabolismo , Simulação de Acoplamento Molecular , Polissacarídeos/química , Polissacarídeos/metabolismo , Conformação Proteica , Relação Estrutura-Atividade , alfa-Amilases/química , alfa-Amilases/metabolismo , alfa-Glucosidases/química
10.
Molecules ; 24(4)2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30769933

RESUMO

Anti-α-glucosidase (AAG) compounds have received great attention due to their potential use in treating diabetes. In this study, Bacillus licheniformis TKU004, an isolated bacterial strain from Taiwanese soil, produced AAG activity in the culture supernatant when squid pens were used as the sole carbon/nitrogen (C/N) source. The protein TKU004P, which was isolated from B. licheniformis TKU004, showed stronger AAG activity than acarbose, a commercial anti-diabetic drug (IC50 = 0.1 mg/mL and 2.02 mg/mL, respectively). The molecular weight of TKU004P, determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), was 29 kDa. High-performance liquid chromatography (HPLC) analysis showed that TKU004P may be a protease that demonstrates AAG activity by degrading yeast α-glucosidase. Among the four chitinous sources of C/N, TKU004P produced the highest AAG activity in the culture supernatant when shrimp head powder was used as the sole source (470.66 U/mL). For comparison, 16 proteases, were investigated for AAG activity but TKU004P produced the highest levels. Overall, the findings suggest that TKU004P could have applications in the biochemical and medicinal fields thanks to its ability to control the activity of α-glucosidase.


Assuntos
Bacillus licheniformis/metabolismo , Endopeptidases/metabolismo , Inibidores de Glicosídeo Hidrolases/metabolismo , alfa-Glucosidases/metabolismo , Bacillus licheniformis/enzimologia , Cromatografia , Cromatografia Líquida de Alta Pressão , Eletroforese em Gel de Poliacrilamida , Endopeptidases/química , Ativação Enzimática , Estabilidade Enzimática , Inibidores de Glicosídeo Hidrolases/química , Concentração de Íons de Hidrogênio , Peso Molecular , Proteólise , alfa-Glucosidases/química
11.
Biomed Chromatogr ; 33(7): e4508, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30743317

RESUMO

Gastrodia elata (G. elata), as a natural plant with nourishing and edible value, plays a vital role in food and pharmaceutical production. In the present study, a novel approach for the simultaneous determination of six components based on high-performance liquid chromatography (HPLC) coupled with photodiode array detection (PDA) was developed for the quality evaluation of G. elata from different regions. Meanwhile, antioxidant and α-glucosidase inhibitory activities were estimated and compared. The results indicated that the total contents of the six compounds in G. elata from Guizhou and Zhejiang provinces obtained by boiling were higher than those obtained by steaming in Anhui and Yunnan provinces. In addition, samples from Guizhou, Yunnan and Shanxi provinces contained more p-hydroxybenzyl alcohol, and always possessed higher antioxidant activity, while samples collected from Anhui province showed the highest α-glucosidase inhibitory activity with the highest gastrodin content. The results revealed that the quality of G. elata was affected by different regions and different initial processing technologies, which provided a reference for the selection and application of G. elata.


Assuntos
Antioxidantes , Cromatografia Líquida de Alta Pressão/métodos , Gastrodia/química , Inibidores de Glicosídeo Hidrolases , Extratos Vegetais/química , Antioxidantes/análise , Antioxidantes/química , Antioxidantes/metabolismo , Inibidores de Glicosídeo Hidrolases/análise , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/metabolismo , Reprodutibilidade dos Testes , alfa-Glucosidases/metabolismo
12.
Comput Biol Chem ; 76: 61-66, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29957363

RESUMO

Neolignans are a large group of polyphenols found in plants and exhibit a wide range of bioactivities including cytotoxicity, apoptosis inducer, antimalarial and antifungal effects, acetylcholinesterase, tyrosinase, and α-glucosidase inhibition. In this study we tested acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), tyrosinase, and α-glucosidase inhibitory effects of a rare neolignan, (-)-4-O-methyldehydrodiconiferyl alcohol 9'-O-ß-glucopyranoside (1) in search for its new pharmaceutical effects. This compound exhibited good tyrosinase inhibition with an IC50 value of 44.62 ±â€¯3.99 µg/mL. Enzyme kinetics and molecular modelling studies were performed to provide insights into its tyrosinase inhibition mechanism.


Assuntos
Benzofuranos/química , Inibidores da Colinesterase/química , Inibidores de Glicosídeo Hidrolases/química , Lignanas/química , Monofenol Mono-Oxigenase/antagonistas & inibidores , Acarbose/química , Agaricales/enzimologia , Benzofuranos/metabolismo , Sítios de Ligação , Inibidores da Colinesterase/metabolismo , Galantamina/química , Inibidores de Glicosídeo Hidrolases/metabolismo , Cinética , Lignanas/metabolismo , Simulação de Acoplamento Molecular , Ligação Proteica , Pironas/química
13.
Food Chem ; 264: 189-198, 2018 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-29853365

RESUMO

There are both soluble and insoluble-bound forms of phenolics in tea-leaf products. In order to increase total soluble phenolics contents, guava leaves tea (GLT) was first fermented with Monascus anka and Saccharomyces cerevisiae, and then hydrolyzed with complex enzymes. The changes in phenolics profiles, antioxidant activities and inhibitory effect on α-glucosidase in processed GLT were investigated. Compared with the un-fermented GLT, fermentation and complex enzymatic processing (FE) significantly increased the total phenolics, total flavonoids, quercetin and kaempferol contents by 2.1, 2.0, 13.0 and 6.8 times, respectively. After the FE, a major proportion of phenolics existed in the soluble form. Quercetin was released in the highest amount among different phenolics. In addition, soluble phenolic extracts from GLT following FE exhibited a highest antioxidant activity and inhibitory effect on α-glucosidase. The paper suggested an improved method for processing GLT into high-value products rich in phenolics and flavonoids aglycones with enhanced health benefits.


Assuntos
Antioxidantes/farmacologia , Flavonoides/metabolismo , Fenóis/metabolismo , Psidium/química , Chás de Ervas , Antioxidantes/análise , Antioxidantes/metabolismo , Fermentação , Flavonoides/análise , Manipulação de Alimentos/métodos , Inibidores de Glicosídeo Hidrolases/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Hidrólise , Fenóis/análise , Folhas de Planta/química , Folhas de Planta/metabolismo , Psidium/metabolismo , Quercetina/análise , Quercetina/metabolismo , Solubilidade , Chás de Ervas/análise
14.
Bioorg Med Chem ; 26(12): 3370-3378, 2018 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-29776833

RESUMO

Xanthone derivatives have shown good α-glucosidase inhibitory activity and have drawn increased attention as potential anti-diabetic compounds. In this study, a series of novel oxazolxanthones were designed, synthesized, and investigated as α-glucosidase inhibitors. Inhibition assays indicated that compounds 4-21 bearing oxazole rings exhibited up to 30-fold greater inhibitory activity compared to their corresponding parent compound 1b. Among them, compounds 5-21 (IC50 = 6.3 ±â€¯0.4-38.5 ±â€¯4.6 µM) were more active than 1-deoxynojirimycin (IC50 = 60.2 ±â€¯6.2 µM), a well-known α-glucosidase inhibitor. In addition, the kinetics of enzyme inhibition measured by using Lineweaver-Burk analysis shows that compound 4 is a competitive inhibitor, while compounds 15, 16 and 20 are non-competitive inhibitors. Molecular docking studies showed that compound 4 bound to the active site pocket of the enzyme while compounds 15, 16, and 20 did not. More interestingly, docking simulations reveal that some of the oxazolxanthone derivatives bind to different sites in the enzyme. This prediction was further confirmed by the synergetic inhibition experiment, and the combination of representative compounds 16 and 20 at the optimal ratio of 4:6 led to an IC50 value of 1.9 ±â€¯0.7 µM, better than the IC50 value of 7.1 ±â€¯0.9 µM for compound 16 and 8.6 ±â€¯0.9 µM for compound 20.


Assuntos
Inibidores de Glicosídeo Hidrolases/síntese química , Xantonas/química , Sítios de Ligação , Domínio Catalítico , Inibidores de Glicosídeo Hidrolases/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Ligações de Hidrogênio , Concentração Inibidora 50 , Cinética , Simulação de Acoplamento Molecular , Oxazóis/química , Xantonas/metabolismo , Xantonas/farmacologia , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo
15.
Bioorg Med Chem ; 26(12): 3461-3467, 2018 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-29789207

RESUMO

Phytochemical investigation of the stem bark of Myristica fatua Houtt. led to the isolation of a new compound 1 (3-tridecanoylbenzoic acid), along with six known acylphenols (2-7). All the compounds displayed moderate inhibitory activity on α-amylase and significant activity on α-glucosidase; however malabaricone B (6) and C (7) were identified as potent α-glucosidase inhibitors with IC50 values of 63.70 ±â€¯0.546, and 43.61 ±â€¯0.620 µM respectively. Acylphenols (compounds 3-7) also showed significant antiglycation property. The molecular docking and dynamics simulation studies confirmed the efficient binding of malabaricone C with C-terminus of human maltase-glucoamylase (2QMJ). Malabaricone B also enhanced the 2-NBDG [2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxy glucose] uptake in L6 myotubes. These findings demonstrate that acylphenols isolated from Myristica fatua Houtt. can be considered as a lead scaffold for the treatment of type II diabetes mellitus.


Assuntos
Inibidores de Glicosídeo Hidrolases/química , Hipoglicemiantes/química , Myristicaceae/química , Compostos Fitoquímicos/química , Sítios de Ligação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/patologia , Inibidores de Glicosídeo Hidrolases/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Humanos , Hipoglicemiantes/metabolismo , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Simulação de Dinâmica Molecular , Células Musculares/citologia , Células Musculares/efeitos dos fármacos , Células Musculares/metabolismo , Myristicaceae/metabolismo , Compostos Fitoquímicos/metabolismo , Compostos Fitoquímicos/farmacologia , Casca de Planta/química , Casca de Planta/metabolismo , Extratos Vegetais/química , Caules de Planta/química , Caules de Planta/metabolismo , Estrutura Terciária de Proteína , Resorcinóis/química , Resorcinóis/metabolismo , Resorcinóis/farmacologia , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo
16.
Mar Drugs ; 16(3)2018 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-29517987

RESUMO

Chitosanases and proteases have received much attention due to their wide range of applications. Four kinds of chitinous materials, squid pens, shrimp heads, demineralized shrimp shells and demineralized crab shells, were used as the sole carbon and nitrogen (C/N) source to produce chitosanases, proteases and α-glucosidase inhibitors (αGI) by four different strains of Paenibacillus. Chitosanase productivity was highest in the culture supernatants using squid pens as the sole C/N source. The maximum chitosanase activity of fermented squid pens (0.759 U/mL) was compared to that of fermented shrimp heads (0.397 U/mL), demineralized shrimp shells (0.201 U/mL) and demineralized crab shells (0.216 U/mL). A squid pen concentration of 0.5% was suitable for chitosanase, protease and αGI production via Paenibacillus sp. TKU042. Multi-purification, including ethanol precipitation and column chromatography of Macro-Prep High S as well as Macro-Prep DEAE (diethylaminoethyl), led to the isolation of Paenibacillus sp. TKU042 chitosanase and protease with molecular weights of 70 and 35 kDa, respectively. For comparison, 16 chitinolytic bacteria, including strains of Paenibacillus, were investigated for the production of chitinase, exochitinase, chitosanase, protease and αGI using two kinds of chitinous sources.


Assuntos
Reatores Biológicos/microbiologia , Decapodiformes/química , Glicosídeo Hidrolases/metabolismo , Paenibacillus/metabolismo , Peptídeo Hidrolases/metabolismo , Animais , Quitina/metabolismo , Quitinases/isolamento & purificação , Quitinases/metabolismo , Crustáceos/química , Fermentação , Inibidores de Glicosídeo Hidrolases/metabolismo , Glicosídeo Hidrolases/isolamento & purificação , Peptídeo Hidrolases/isolamento & purificação
17.
Int J Biol Macromol ; 113: 212-218, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29477543

RESUMO

Inhibition of α-glucosidase is directly associated with treatment of type 2 diabetes. In this regard, we conducted enzyme kinetics integrated with computational docking simulation to assess the inhibitory effect of raspberry ketone (RK) on α-glucosidase. RK bound to the active site of α-glucosidase and interacted with several key residues such as ASP68, TYR71, HIS111, PHE157, PHE158, PHE177, GLN181, ASP214, THR215, ASP349, ASP408, and ARG439, as detected by protein-ligand docking simulation. Subsequently, we confirmed the action of RK on α-glucosidase as the non-competitive type of inhibition in a reversible and rapidly binding manner. The relevant kinetic parameters were IC50=6.17±0.46mM and Ki=7.939±0.211mM. Regarding the structure-activity relationship, the higher concentration of RK induced slight modulation of the shape of the active site as monitored by hydrophobic exposure. The tertiary conformational change was linked to RK inhibition, and mostly involved regional changes of the active site. Our study provides insight into the functional role of RK due to its structural property of a hydroxyphenyl ring that interacts with the active site of α-glucosidase. We suggest that similar hydroxyphenyl ring compounds targeting the key residues of the active site might be potential α-glucosidase inhibitors.


Assuntos
Butanonas/metabolismo , Butanonas/farmacologia , Inibidores de Glicosídeo Hidrolases/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Simulação de Acoplamento Molecular , alfa-Glucosidases/metabolismo , Cinética , Conformação Proteica , Saccharomyces cerevisiae/enzimologia , alfa-Glucosidases/química
18.
Bioorg Med Chem ; 26(3): 737-746, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29306546

RESUMO

Cratoxylum cochinchinense displayed significant inhibition against protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase, both of which are key target enzymes to attenuate diabetes and obesity. The compounds responsible for both enzymes inhibition were identified as twelve xanthones (1-12) among which compounds 1 and 2 were found to be new ones. All of them simultaneously inhibited PTP1B with IC50s of (2.4-52.5 µM), and α-glucosidase with IC50 values of (1.7-72.7 µM), respectively. Cratoxanthone A (3) and γ-mangostin (7) were estimated to be most active inhibitors against both PTP1B (IC50 = 2.4 µM for 3, 2.8 µM for 7) and α-glucosidase (IC50 = 4.8 µM for 3, 1.7 µM for 7). In kinetic studies, all isolated xanthones emerged to be mixed inhibitors of α-glucosidase, whereas they behaved as competitive inhibitors of PTP1B. In time dependent experiments, compound 3 showed isomerization inhibitory behavior with following kinetic parameters: Kiapp = 2.4 µM; k5 = 0.05001 µM-1 S-1 and k6 = 0.02076 µM-1 S-1.


Assuntos
Clusiaceae/química , Inibidores Enzimáticos/química , Inibidores de Glicosídeo Hidrolases/química , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Xantonas/química , alfa-Glucosidases/metabolismo , Clusiaceae/metabolismo , Ensaios Enzimáticos , Inibidores Enzimáticos/metabolismo , Inibidores de Glicosídeo Hidrolases/metabolismo , Humanos , Concentração Inibidora 50 , Cinética , Espectroscopia de Ressonância Magnética , Conformação Molecular , Raízes de Plantas/química , Raízes de Plantas/metabolismo , Ligação Proteica , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Xantonas/isolamento & purificação , Xantonas/metabolismo , alfa-Glucosidases/química
19.
BMC Complement Altern Med ; 18(1): 1, 2018 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-29295712

RESUMO

BACKGROUND: The medicinal importance of a novel plant Olax nana Wall. ex Benth. (family: Olacaceae) was revealed for the first time via HPLC-DAD finger printing, qualitative phytochemical analysis, antioxidant, cholinesterase, and α-glucosidase inhibitory assays. METHODS: The crude methanolic extract of O. nana (ON-Cr) was subjected to qualitative phytochemical analysis and HPLC-DAD finger printing. The antioxidant potential of ON-Cr was assessed via 1,1-diphenyl,2-picrylhydrazyl (DPPH), 2,2-azinobis[3-ethylbenzthiazoline]-6-sulfonic acid (ABTS) and hydrogen peroxide (H2O2) free radical scavenging assays. Furthermore, acetylcholinesterase (AChE) & butyrylcholinesterase (BChE) inhibitory activities were performed using Ellman's assay, while α- glucosidase inhibitory assay was carried out using a standard protocol. RESULTS: The qualitative phytochemical analysis of ON-Cr revealed the presence of secondary metabolites like alkaloids, flavonoids, tannins, sterols, saponins and terpenoids. The HPLC-DAD finger printing revealed the presence of 40 potential compounds in ON-Cr. Considerable anti-radical activities was revealed by ON-Cr in the DPPH, ABTS and H2O2 free radical scavenging assays with IC50 values of 71.46, 72.55 and 92.33 µg/mL, respectively. Furthermore, ON-Cr showed potent AChE and BChE inhibitory potentials as indicated by their IC50 values of 33.2 and 55.36 µg/mL, respectively. In the α-glucosidase inhibition assay, ON-Cr exhibited moderate inhibitory propensity with an IC50 value of 639.89 µg/mL. CONCLUSIONS: This study investigated Olax nana for the first time for detailed qualitative phytochemical tests, HPLC-DAD finger printing analysis, antioxidant, anticholinesterase and α-glucosidase inhibition assays. The antioxidant and cholinesterase inhibitory results were considerable and can provide scientific basis for further studies on the neuroprotective and anti-Alzheimer's potentials of this plant. ON-Cr may further be subjected to fractionation and polarity guided fractionation to narrow down the search for isolation of bioactive compounds.


Assuntos
Antioxidantes/análise , Inibidores da Colinesterase/análise , Cromatografia Líquida de Alta Pressão/métodos , Inibidores de Glicosídeo Hidrolases/análise , Olacaceae/química , Extratos Vegetais/análise , Antioxidantes/química , Antioxidantes/metabolismo , Benzotiazóis/análise , Benzotiazóis/metabolismo , Compostos de Bifenilo/análise , Compostos de Bifenilo/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/metabolismo , Peróxido de Hidrogênio/análise , Peróxido de Hidrogênio/metabolismo , Picratos/análise , Picratos/metabolismo , Extratos Vegetais/química , Extratos Vegetais/metabolismo , Ácidos Sulfônicos/análise , Ácidos Sulfônicos/metabolismo
20.
J Sep Sci ; 41(7): 1704-1710, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29293286

RESUMO

Radix Scutellaria is a widely used traditional Chinese medicine in the treatment of various diseases. However, the activities of the absorbed components and metabolites of its main flavones in rat plasma need further investigation. In this study, a systematic method based on ultra-high performance liquid chromatography with quadruple time-of-flight mass spectrometry was developed to speculate the absorbed components and metabolites of the main flavonoids in Radix Scutellaria extract in rat plasma sample after oral administration of the extract. Twelve compounds, including four prototype components and eight metabolites, were confirmed in drug-containing plasma. In these metabolites, five were originally detected in rat plasma. The possible metabolic pathways of these polyhydroxy flavones in vivo were described and clarified. Microdialysis with intensity-fading mass spectrometry was originally employed to investigate the binding affinities of the absorbed components and metabolites with α-glucosidase. The order of their binding affinities was P4 > P3 > P2 > P1≥M5 > M3 > M1. The research result is helpful to deepen the understanding of the absorbed components and metabolic pathways of main flavones from Radix Scutellaria, and provide a new approach to screen potential inhibitors from in vivo components originated from Chinese herb.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Flavonoides/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Extratos Vegetais/farmacologia , Administração Oral , Animais , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/metabolismo , Flavonoides/administração & dosagem , Flavonoides/metabolismo , Inibidores de Glicosídeo Hidrolases/administração & dosagem , Inibidores de Glicosídeo Hidrolases/metabolismo , Masculino , Espectrometria de Massas , Medicina Tradicional Chinesa , Microdiálise , Extratos Vegetais/administração & dosagem , Extratos Vegetais/metabolismo , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Fatores de Tempo , alfa-Glucosidases/metabolismo
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