Glycosidase Inhibitory Activity Research Articles

A practical synthesis of nitrone-derived C5a-functionalized isofagomines as protein stabilizers to treat Gaucher disease.

Isofagomine (IFG) and its analogues possess promising glycosidase inhibitory activities. However, a flexible synthetic strategy toward both C5a-functionalized IFGs remains to be explored. Here we show a practical synthesis of C5a-S and R aminomethyl IFG-based derivatives via the diastereoselective addition of cyanide to cyclic nitrone 1. Nitrone 1 was conveniently prepared on a gram scale and in high yield from inexpensive (-)-diethyl D-tartrate via a straightforward method, with a stereoselective Michael addition of a nitroolefin and a Nef reaction as key steps. A 268-membered library (134 × 2) of the C5a-functionalized derivatives was submitted to enzyme- or cell-based bio-evaluations, which resulted in the identification of a promising β-glucocerebrosidase (GCase) stabilizer demonstrating a 2.7-fold enhancement at 25 nM in p.Asn370Ser GCase activity and a 13-fold increase at 1 μM in recombinant human GCase activity in Gaucher cell lines.

Synthesis, glycosidase inhibitory activity and computational studies of dideoxymethylnojirimycin and its derivatives

We report here the synthesis and biological evaluation of dideoxynojirimycin and its analogs and their functional effect on glucosidase enzyme inhibition against α-glucosidase(yeast), α-galactosidase and β-galactosidase (kluyveromyces lactis). All the compounds significantly inhibited the α-glucosidase(yeast) activity when compared to DNJ and shown strong inhibition against β-galactosidase (kluyveromyces lactis) when compared to DNJ. The molecular docking studies also reveals that these compounds showing strong ligand binding energies against yeast-ɑ-glucosidase- I, yeast β-galactosidase and human lysosomal acid–ɑ-glucosidase. Interestingly the analogues having N-H, N-alkyl and N-benzyl group along with ethyl group significantly inhibited the β-galactosidase activity when compared to DNJ. The in-silico studies are in correlation with invitro activity data; therefore, this study will be useful to develop further glycosidase inhibitors.

Synthesis of the Purported Structure of Glyphaeaside C and Proposed Revisions to the Structures of the Glyphaeaside Alkaloids.

The 10 glyphaeaside alkaloids isolated from the roots of Glyphaea brevis were originally purported as piperidine-based 1-C-alkylated iminosugars, with the A-, B-, and C-type glyphaeasides bearing l-DFJ, DGJ, and DNJ ring configurations, respectively. Subsequent investigations have revealed glyphaeaside C as being a pyrrolidine-based iminosugar with a DMDP ring configuration via total synthesis of the revised structure. In this work, side chain diastereomers of the originally purported structure of glyphaeaside C (10) and two related α-1-C-alkylated DNJ derivatives were synthesized from a common precursor, which was prepared in turn via stereoselective Grignard addition to a protected d-glycosylamine, followed by a reductive amination-cyclization sequence. Glycosidase inhibitory activity studies revealed general structure 10 as having potent inhibition against various α-glucosidases and weak inhibition against almond β-glucosidase in agreement with similar DNJ-based iminosugars and in contrast to natural glyphaeaside C, suggesting that the (1,2-dihydroxy-3-phenyl)propyl moiety does not play a particularly vital role in the inhibitory modes of action of either compound. Furthermore, the absolute configuration of natural glyphaeaside C was proposed as that of d-DMDP, and the structures of the A- and B-type glyphaeasides were revised as 1-deoxy-DALDP and DALDP derivatives, respectively, based on interpretation of their reported NMR spectroscopic data.

Phytochemical cocktail of Asanadi ganaextract in the management of diabetes.

It is of interest to investigate that the phytochemical analysis, in-vitro antioxidant potential and glycosidase inhibitory potential of Asanadi ganaa polyherbal formulation. Asanadi ganais a classical Ayurvedic polyherbal formulation, markedly used for alleviation of Prameha and Medodosha, which correlates in many ways with obesity, metabolic syndrome, and diabetes mellitus (madhumeha). The phytochemical constituents, total phenolic, total flavonoids, total tannin content, total antioxidant capacity, total reducing power, and free radical scavenging activity of the polyherbal formulation extracts were determined. Comparing it to the common medication Acarbose, its inhibitory impact against the digestive enzymes α-amylase and α-glucosidase was also examined. The formulation showed the presence of major constituents such as terpenoids, triterpenoids, sterols, flavonoids, tannins, phenolic, saponins, alkaloids and Glycosides. The ethanol extract had high phenolic content and flavonoid content, whereas the aqueous extract had more tannin content (181 ± 5.5µg/mg), (132 ± 5.50 µg/mg), (22± 1.6 µg/mg respectively. we conclude that the extracts of ayurvedic polyherbal formulations, particularly ethanol extract are a potential source of natural antioxidants and remarkable glycosidase inhibitory activity. Hence, Asanadi ganahas the potential to be a safe and effective natural treatment for the delay or prevention of diabetic complications.

Dietary Supplement of Amomum villosum Lour. Polysaccharide Attenuates Ulcerative Colitis in BALB/c Mice.

Amomum villosum Lour. (A. villosum), a comestible medicinal plant, has been traditionally used in China to treat diarrhea, stomach fullness, and abdominal distension. Polysaccharide, the main chemical component of A. villosum, has been shown to possess potential antioxidant and glycosidase inhibitory activities; however, whether it has anticolitis activity is unknown. The aim of this research was to evaluate the anticolitis effects of A. villosum polysaccharide (AVLP) in BALB/c mice. The results showed that AVLP administration significantly reversed body weight loss, colon shortening and colon weight gain and decreased the levels of proinflammatory cytokines and chemokines in colitis mice (p < 0.05). AVLP administration also maintained intestinal barrier function by the upregulation of ZO-1 protein expression (p < 0.05). In addition, high-throughput sequencing analysis showed that AVLP possessed a great regulatory effect on the growth of Adlercreutzia, Clostridium, Streptococcus, Parabacteroides, Helicobacter, Odoribacter, and Alistipes (p < 0.05, LDA score > 2). The correlation analysis revealed that the protective effects against colitis of AVLP were highly correlated with intestinal bacterium regulation. These results suggest that AVLP intake could serve as a prospective nutritional strategy for inflammatory bowel diseases.

Selenium-Enriched and Ordinary Black Teas Regulate the Metabolism of Glucose and Lipid and Intestinal Flora of Hyperglycemic Mice.

Black tea is one of the six major tea categories and has a variety of bioactivities. However, little is known about its comprehensive evaluation of hypoglycemic effects and potential mechanisms. In this study, we investigated the in vivo hypoglycemic activity and potential mechanism for aqueous extracts of ordinary black tea (BT) and selenium-enriched black tea (Se-BT) by using an established high-fat diet together with streptozotocin (STZ)-induced hyperglycemic mouse model. Additionally, we also explored their α-glucosidase inhibition activity. The results show that both BT and Se-BT had a favorable glycosidase inhibitory activity. Moreover, the intervention of BT and Se-BT could regulate the mRNA expression and the level of serum parameters related to glucose and lipid metabolisms. Accordingly, they could activate the phosphoinositide-3-kinase/protein kinase B (PI3K/Akt) signaling pathway and alleviate insulin resistance (IR) and hyperglycemia. Moreover, supplementation of BT and Se-BT increased the richness and diversity of intestinal flora and altered the abundance of beneficial and harmful bacteria. Both BT and Se-BT could regulate glucose metabolism, alleviate tissue damage, and restore intestinal flora dysbiosis, suggesting that they could be used as a natural functional food for preventing hyperglycemia.

Studies towards the synthesis of polyhydroxylated pyrrolidine alkaloids isolated from Broussonetia kazinoki (moraceae)

The syntheses of L-AB1, L-DMDP, and the novel compounds, (−)-phenethyl-L-AB1, (−)-10′-deoxobroussonetine C, (−)-10′-deoxobroussonetine E, (−)-1′-epi-10′-deoxobroussonetine E, and (−)-(6S)-12′-hydroxydodecylmoranoline are reported. These syntheses start from d-xylose employing the Petasis borono-Mannich reaction to stereoselectively introduce the amino group, followed by a chemo- and regioselective O-mesylation to deliver the fully functionalized pyrrolidine moiety after intramolecular SN2-cyclisation. The synthesis of the latter targeted compound involved a ring expansion process of a prolinol moiety to a piperidine derivative under Mitsunobu reaction conditions. An attempted synthesis of desired ent-broussonetine C was unsuccesful due to formation of an unexpected tetrahydrofuran derivative in the final stage of the synthesis. The glycosidase inhibitory activities of four of the new target compounds against a panel of ten glycosidaes is also presented.

Synthesis of 6-Halo-Substituted Pericosine A and an Evaluation of Their Antitumor and Antiglycosidase Activities.

The enantiomers of 6-fluoro-, 6-bromo-, and 6-iodopericosine A were synthesized. An efficient synthesis of both enantiomers of pericoxide via 6-bromopericosine A was also developed. These 6-halo-substituted pericosine A derivatives were evaluated in terms of their antitumor activity against three types of tumor cells (p388, L1210, and HL-60) and glycosidase inhibitory activity. The bromo- and iodo-congeners exhibited moderate antitumor activity similar to pericosine A against the three types of tumor cell lines studied. The fluorinated compound was less active than the others, including pericosine A. In the antitumor assay, no significant difference in potency between the enantiomers was observed for any of the halogenated compounds. Meanwhile, the (−)-6-fluoro- and (−)-6-bromo-congeners inhibited α-glucosidase to a greater extent than those of their corresponding (+)-enantiomers, whereas (+)-iodopericosine A showed increased activity when compared to its (−)-enantiomer.

Two novel enantiomers from metarhizium flavoviride and their inhibitory activities against α-glucosidase

A pair of novel enantiomers metarrhiziumoids A (R-enantiomer, 14.3 mg) and B (S-enantiomer, 9.5 mg) were isolated from 3.0 g extract of Metarhizium flavoviride by silica gel column chromatography combined with preparative and semi-preparative HPLC, and identified with high resolution mass, 1D, 2D NMR and circular dichroism. Targets prediction showed that the two compounds had glycosidase inhibitory activity. Result of α-glycosidase inhibitory tests showed that the both enantiomers were competitive inhibitors of α-glycosidase, and the bioactivity of metarrhiziumoids B (IC50 = 174 μg/mL) was stronger than that of metarrhiziumoids A (IC50 = 259 μg/mL). Molecular docking results show that the two enantiomers have different optimal docking modes and the binding energy for the S-enantiomer (-7.8 kcal/mol) was lower than for the R-enantiomer (-7.20 kcal/mol). The docking mode selections and binding energy differences resulted in the inhibitory activity difference.

Hypoglycemic ingredients identification of Rheum tanguticum Maxim. ex Balf. by UHPLC-triple-TOF-MS/MS and interrelationships between ingredients content and glycosidase inhibitory activities

Rheum tanguticum Maxim. ex Balf. (RT), mainly is mainly produced in Gansu, Qinghai, Tibet and Sichuan of China, has long been used as a medicine for purging fire and quenching thirst. The RTR-2 (Rheum tanguticum root extract without polysaccharides and protein) had strong inhibitory activities against a-amylase, maltase and sucrase with the IC50 0.042 mg/mL, 0.124 mg/mL and 0.097 mg/mL, respectively. In addition, RTR-2 could significantly reduce PBG level of diabetic mice in starch/maltose/sucrose tolerance test. Total 48 constituents including 12 anthraquinones, 4 bianthrones, 8 flavans, 3 stilbenes, 5 phenylbutanones, 4 naphthosides, 8 glucose gallates and 4 phenolic acids were determined in RTR-2 by UPLC-Triple-TOF/MS analysis of molecular ion, main fragments, retention time, and references. Furthermore, the components such as flavan ((-)-epicatechin 3-O-gallate) and phenylbutanone (lindleyin) were demonstrated to have sucrase and maltase inhibitory activites, and might be the main hypoglycemic active ingredients of RTR-2 extract. All these results offered an exhaustive knowledge for the hypoglycemic compounds of Rheum tanguticum, which was conducive to its further development and utilization as a valuable source of hypoglycemic plant in pharmaceutical industry.

Enhancing the In Vitro Biological Activity of Degraded Silk Sericin and Its Analog Metabolites.

Two sericins of high and low molecular weight (HS and LS) were prepared from commercial silkworm cocoon silk with a boiling water and Ca(OH)2 solution with ultrasonic treatments, respectively. This study first investigated the release concentration of the two abovementioned sericins in simulated saliva, gastric juice, and intestinal juice (pH 6.8, 2.0, and 7.4, respectively) within 10 h. The results showed that the order of sericin release rate and its amount in the simulated environment was gastric juice > saliva > intestinal juice. Second, the molecular weights of both sericin metabolites formed by in vitro enzymatic degradation were lower than 15 kDa. The α-glucosidase inhibitory activities of both sericins and their analog metabolites were positively correlated with their concentrations. The IC50 values of the HS- and LS-derived metabolites were 1.02 ± 0.12 mg/mL and 0.91 ± 0.15 mg/mL, respectively, which were five to seven times lower than those of both original sericins. The total antioxidant capacities and hydroxyl radical scavenging capacities of both metabolites were enhanced by one- to three-fold compared with HS and LS. These results indicate that both sericins, regardless of molecular size, have significantly enhanced antioxidant, superoxide free radical scavenging, and glycosidase inhibitory activities after simulated metabolism, and that LS is better than HS regardless of simulated digestion. These results confirm that sericin is important in the sustainable development and utilization of silk resources, especially the reduction in environmental pollution, and provides new ideas for the development of adjuvant treatments for diabetes and the development of foods with anti-hyperglycemic functions.

Herbal formuLation of Azadirachta indica and Stevia rebaudiana and Its Anti-inflammatory and Anti-Diabetic Activity

Introduction: Azadirachta indica, a natural herb also called Neem, and its seed extract has various medicinal uses. Neem also possesses notable insecticidal and pesticide activities. On the other hand, Stevia rebaudiana extract has alpha amylase glycosidase inhibitory activity, which contrasts with traditional wheat bread. This last plant can also regulate blood glucose levels, and prevent hypertension and caries.
 Aim: This study aimed to analyse the anti-diabetic and anti-inflammatory activities of Azadirachta indica and stevia rebaudiana.
 Materials and Methods: 2.5 g from Azadirachta indica and Stevia rebaudiana plants mixed with 100 mL of distilled water were boiled. The final extract was then filtered using Whatman filter paper. Spearman correlation analysis was done by SPSS. Positive correlation analysis level of significance was set as r=1.
 Results: The anti-diabetic activity and anti-inflammatory activities of Azadirachta indica and Stevia rebaudiana extracts showed positive spearman correlations (r = 1). Both activities happen in a dose-dependent manner, being higher with the increasing of the concentration and of the absorbance values.
 Conclusion: Through this study, it was possible to conclude that Azadirachta indica and Stevia rebaudiana have great anti-inflammatory and anti-diabetic activities and can be used as a possible alternative drug for attenuating inflammation and preventing diabetic complications.

New α-galactosidase-inhibiting aminohydroxycyclopentanes.

A set of cyclopentanoid α-galactosidase ligands was prepared from a partially protected ω-eno-aldose via a reliable (2 + 3)-cycloaddition protocol with slightly modified conditions. The obtained N-benzylisoxazolidine ring was selectively opened and the configuration of the hydroxymethylgroup was inverted. Consecutive deprotection provided an aminocyclopentane, which was N-alkylated to furnish a set of potential α-galactosidase inhibitors. Their glycosidase inhibitory activities were screened with a panel of standard glycosidases of biological significance.

Structural characterization, anti-inflammatory and glycosidase inhibitory activities of two new polysaccharides from the root of Pueraria lobata.

Diabetes seriously endangers public health and brings a heavy economic burden to the country. Inflammation is one of the main inducing factors of type-2 diabetes (T2D) and may cause some complications of diabetes, such as diabetic encephalopathy and peripheral neuropathy. In-depth research and development of drugs to cure diabetes and complications are of great significance. Pueraria lobate is a medicinal herb used in several countries to treat many diseases. Here, two new polysaccharides (PLB-1-1 and PLB-1-2) were isolated and purified from the root of Pueraria lobata with molecular weights of 9.1 × 103 Da and 3.8 × 103 Da, respectively. The structure was evaluated by monosaccharide composition, GC-MS and NMR spectroscopy. It was determined that PLB-1-1 comprised →4)-α-d-Glcp-(1→, α-d-Glcp-(1→, →6)-β-d-Galp-(1→, →3)-α-l-Araf-(1→, →3,6)-β-d-Manp-(1→ and →4,6)-β-d-Manp-(1→, and PLB-1-2 consisted of →4)-α-d-Glcp-(1→, β-d-Glcp-(1→, →4,6)-β-d-Glcp-(1→, →3,6)-β-d-Manp-(1→ and α-l-Fucp-(1→. Furthermore, both PLB-1-1 and PLB-1-2 showed anti-inflammatory and inhibitory activities of α-glucosidase and α-amylase in vitro. Therefore, the new polysaccharides, i.e., PLB-1-1 and PLB-1-2, may be considered candidates for the treatment of diabetes and its related complications.

Syntheses and Glycosidase Inhibitory Activities, and in Silico Docking Studies of Pericosine E Analogs Methoxy-Substituted at C6.

Inspired by the significant α-glucosidase inhibitory activities of (+)- and (−)-pericosine E, we herein designed and synthesized 16 analogs of these marine natural products bearing a methoxy group instead of a chlorine atom at C6. Four of these compounds exhibited moderate α-glucosidase inhibitory activities, which were weaker than those of the corresponding chlorine-containing species. The four compounds could be prepared by coupling reactions utilizing the (−)-pericosine B moiety. An additional in silico docking simulation suggested that the reason of reduced activity of the C6-methoxylated analogs might be an absence of hydrogen bonding between a methoxy group with the surrounding amino acid residues in the active site in α-glucosidase.

The Synthesis and Glycosidase Inhibitory Activity of Analogues of Tiruchanduramine

The Synthesis and Glycosidase Inhibitory Activity of Analogues of Tiruchanduramine

Nutraceutical Potential of Five Mexican Brown Seaweeds.

In search of pharmaceutically active products to control type 2 diabetes, five brown seaweeds (Silvetia compressa, Cystoseira osmundacea, Ecklonia arborea, Pterygophora californica, and Egregia menziesii) from the Northwest Mexican Pacific coast were investigated. Proximate composition and total polyphenol content (TPC) as phloroglucinol equivalents (PGE) were determined for the five seaweed powders and their respective hydroethanolic (1 : 1) extracts. Extracts were screened for their radical scavenging activity (DPPH and ORAC) and glycosidase inhibitory activity. HPLC-DAD, HPLC-MS-TOF, and ATR-FT-IR methodologies were used to identify the most abundant phlorotannins and sulfated polysaccharides in the extracts. Hydroethanolic extracts contained minerals (17 to 59% of the dry matter), proteins (4 to 9%), ethanol-insoluble polysaccharides (5.4 to 53%), nitrogen-free extract (NFE) (24.4 to 70.1%), lipids (5 to 12%), and TPC (2.6 to 47.7 g PGE per 100 g dry extract). S. compressa and E. arborea dry extracts presented the lowest ash content (26 and 17%, respectively) and had some of the highest phenolic (47.7 and 15.2 g PGE per 100 g extract), NFE (57.3 and 70.1%), and soluble polysaccharide (19.7 and 53%) contents. S. compressa and E. arborea extracts had the highest antioxidant activity (IC50 DPPH 1.7 and 3.7 mg mL−1; ORAC 0.817 and 0.801 mmol Trolox equivalent/g extract) and the highest α-amylase and α-glucosidase inhibitory capacities (IC50 940 and 1152 μg mL−1 against α-amylase and 194 and 647 μg mL−1 against α-glucosidase). The most abundant phlorotannins identified in the extracts were phloretol, fucophloroethol, and two- and three-phloroglucinol unit (PGU) phlorotannins. Laminarin, fucoidan, and alginate were among the sulfated polysaccharides identified in the extracts. The bioactivities of S. compressa and E. arborea extracts were mainly related with their contents of three PGU phlorotannins and sulfated polysaccharides (e.g., fucoidan, laminarin, and alginate). These results suggest S. compressa and E. arborea are potential candidates for food products and nutraceutical and pharmaceutical preparations, and as additives for diabetes management.

Synthesis of tricyclic benzimidazole-iminosugars as potential glycosidase inhibitors via a Mitsunobu reaction

A series of tricyclic benzimidazole-iminosugars 1(a–f) and 2(a–f) were synthesized and evaluated for their their inhibitory activities against five glycosidases. The synthesis initiated from the benzyl protected sugar (aldehyde) 5 that reacted with 1,2-diaminobenzene to afford aldo-benzimidazole 6 by the iodine-induced oxidative condensation. Then, tricyclic compound 7 was obtained in high yields of 73%–87% by the key Mitsunobu reaction through intramolecular cyclization of the unprotected OH and the NH in 6. After removal of the benzyl group in CF3SO3H, the target tricyclic benzimidazole-iminosugars 1 and 2 were achieved. The protocol was effective for the preparation of the tricyclic iminosugar in satisfactory yield. The results of the glycosidase inhibitory activities of 1 and 2 showed that three compounds derived from d-ribose exhibited specific and good inhibitory effects on β-glucosidase. Among them, 1e-1 was the best one with IC50 value of 5.37 μM. All hydroxyl groups on β-position would be favourable to the inhibitory activity of such tricyclic benzimidazole-iminosugars against β-glucosidase.

Thiol-ene "Click" Synthesis and Pharmacological Evaluation of C-Glycoside sp2-Iminosugar Glycolipids.

The unique stereoelectronic properties of sp2-iminosugars enable their participation in glycosylation reactions, thereby behaving as true carbohydrate chemical mimics. Among sp2-iminosugar conjugates, the sp2-iminosugar glycolipids (sp2-IGLs) have shown a variety of interesting pharmacological properties ranging from glycosidase inhibition to antiproliferative, antiparasitic, and anti-inflammatory activities. Developing strategies compatible with molecular diversity-oriented strategies for structure–activity relationship studies was therefore highly wanted. Here we show that a reaction sequence consisting in stereoselective C-allylation followed by thiol-ene “click” coupling provides a very convenient access to α-C-glycoside sp2-IGLs. Both the glycone moiety and the aglycone tail can be modified by using sp2-iminosugar precursors with different configurational profiles (d-gluco or d-galacto in this work) and varied thiols, as well as by oxidation of the sulfide adducts (to the corresponding sulfones in this work). A series of derivatives was prepared in this manner and their glycosidase inhibitory, antiproliferative and antileishmanial activities were evaluated in different settings. The results confirm that the inhibition of glycosidases, particularly α-glucosidase, and the antitumor/leishmanicidal activities are unrelated. The data are also consistent with the two later activities arising from the ability of the sp2-IGLs to interfere in the immune system response in a cell line and cell context dependent manner.

The History of the Glycosidase Inhibiting Hyacinthacine C-type Alkaloids: From Discovery to Synthesis.

Background:The inherent glycosidase inhibitory activity and potentially therapeutic value of the polyhydroxylated pyrrolizidine alkaloids containing a hydroxymethyl substituent at the C-3 position have been well documented. Belonging to this class, the naturally occurring hyacinthacine C-type alkaloids are of general interest among iminosugar researchers. Their selective micromolar α-glycosidase inhibitory ranges (10 – 100 µM) suggest that these azasugars are potential leads for treating type II diabetes. However, the structures of hyacinthacine C1, C3 and C4 are insecure with hyacinthacine C5 being recently corrected.Objective:This review presents the hyacinthacine C-type alkaloids: their first discovery to the most recent advancements on the structures, biological activities and total synthesis.Conclusion:The hyacinthacine C-type alkaloids are of exponentially increasing interest and will undoubtedly continue to be reported as synthetic targets. They represent a challenging but rewarding synthetic feat for the community of those interested in accessing biologically active iminosugars. Since 2009, ten total syntheses have been employed towards accessing similarly related products but only three have assessed the glycosidase inhibitory activity of the final products. This suggests the need for an accessible and universal glycosidase inhibitory assay so to accurately determine the structure-activity relationship of how the hyacinthacine C-type alkaloids inhibit specific glycosidases. Confirming the correct structures of the hyacinthacine C-type alkaloids as well as accessing various analogues continues to strengthen the foundation towards a marketable treatment for type II diabetes and other glycosidase related illnesses.