ABSTRACT
The iminosugar 1-deoxynojirimicyn (DNJ) contained in mulberry leaves has displayed systemic beneficial effects against disorders of carbohydrate metabolism. Nevertheless, its effect is impaired by the short half-life. Alginate-based carriers were developed to encapsulate a DNJ-rich mulberry extract: Ca-alginate beads, obtained by external gelation, and spray-dried alginate microparticles (SDMs). Mean size and distribution, morphology, drug loading, encapsulation efficiency, experimental yield, and release characteristics were determined for the two formulations. Ca-alginate beads and SDMs exhibited an encapsulation efficiency of about 54% and 98%, respectively, and a DNJ loading in the range of 0.43-0.63 µg/mg. The in vitro release study demonstrated the carriers' capability in controlling the DNJ release in acid and basic conditions (<50% in 5 h), due to electrostatic interactions, which were demonstrated by 1H-NMR relaxometry studies. Thus, alginate-based particles proved to be promising strategies for producing food supplements containing mulberry leaf extracts for the management of hyperglycemic state.
Subject(s)
Alginates , Morus , Alginates/metabolism , 1-Deoxynojirimycin/chemistry , Morus/chemistry , Dietary Supplements , Plant Extracts/chemistry , Plant Leaves/metabolismABSTRACT
The alpha (α)-amylase is a calcium metalloenzyme that aids digestion by breaking down polysaccharide molecules into smaller ones such as glucose and maltose. In addition, the enzyme causes postprandial hyperglycaemia and blood glucose levels to rise. α-Amylase is a well-known therapeutic target for the treatment and maintenance of postprandial blood glucose elevations. Various enzymatic inhibitors, such as acarbose, miglitol and voglibose, have been found to be effective in targeting this enzyme, prompting researchers to express an interest in developing potent alpha-amylase inhibitor molecules. The review mainly focused on designing different derivatives of drug molecules such as benzofuran hydrazone, indole hydrazone, spiroindolone, benzotriazoles, 1,3-diaryl-3-(arylamino) propan-1-one, oxadiazole and flavonoids along with their target-receptor interactions, IC50 values and other biological activities.
Subject(s)
Diabetes Mellitus/drug therapy , Glycoside Hydrolase Inhibitors/chemistry , Hypoglycemic Agents/chemistry , alpha-Amylases/metabolism , 1-Deoxynojirimycin/analogs & derivatives , 1-Deoxynojirimycin/chemistry , Acarbose/chemistry , Benzofurans/chemistry , Blood Glucose/drug effects , Drug Discovery , Flavonoids/chemistry , Glycoside Hydrolase Inhibitors/pharmacology , Humans , Hydrazones/chemistry , Hypoglycemic Agents/pharmacology , Indoles/chemistry , Inositol/analogs & derivatives , Inositol/chemistry , Oxadiazoles/chemistry , Structure-Activity RelationshipABSTRACT
1-Deoxynojirimycin (1-DNJ) is the major effective component of mulberry leaves, exhibiting inhibitory activity against α-glucosidase. However, due to the low content of 1-DNJ in mulberry products, its level cannot meet the lowest dose to exhibit its activity. In this study, a combination of dietary 5,6,7-trihydroxy-flavonoid aglycones with 1-DNJ showed synergistic inhibitory activity against maltase of mice α-glucosidase and recombinant C- and N-termini of maltase-glucoamylase (MGAM) and baicalein with 1-DNJ exhibited the strongest synergistic effect. The synergistic effect of the combination was also confirmed by the maltose tolerance test in vivo. Enzyme kinetics, molecular docking, fluorescence spectrum, and circular dichroism spectrometry studies indicated that the major mechanism of the synergism is that baicalein was a positive allosteric inhibitor and bound to the noncompetitive site of MGAM, causing an increase of the binding affinity of 1-DNJ to MGAM. Our results might provide a theoretical basis for the design of dietary supplements containing mulberry products.
Subject(s)
1-Deoxynojirimycin/administration & dosage , Diabetes Mellitus, Type 2/drug therapy , Flavonoids/administration & dosage , Glycoside Hydrolase Inhibitors/administration & dosage , Morus/chemistry , Plant Extracts/administration & dosage , alpha-Glucosidases/metabolism , 1-Deoxynojirimycin/chemistry , Animals , Blood Glucose/metabolism , Diabetes Mellitus, Type 2/enzymology , Diabetes Mellitus, Type 2/metabolism , Drug Synergism , Flavonoids/chemistry , Glucan 1,4-alpha-Glucosidase/antagonists & inhibitors , Glucan 1,4-alpha-Glucosidase/chemistry , Glucan 1,4-alpha-Glucosidase/genetics , Glucan 1,4-alpha-Glucosidase/metabolism , Glycoside Hydrolase Inhibitors/chemistry , Humans , Kinetics , Mice , Mice, Inbred C57BL , Plant Extracts/chemistry , Plant Leaves/chemistry , Postprandial Period/drug effects , alpha-Glucosidases/chemistry , alpha-Glucosidases/geneticsABSTRACT
Iminosugars are sugar analogues endowed with a high pharmacological potential. The wide range of biological activities exhibited by these glycomimetics associated with their excellent drug profile make them attractive therapeutic candidates for several medical interventions. The ability of iminosugars to act as inhibitors or enhancers of carbohydrate-processing enzymes suggests their potential use as therapeutics for the treatment of cystic fibrosis (CF). Herein we review the most relevant advances in the field, paying attention to both the chemical synthesis of the iminosugars and their biological evaluations, resulting from in vitro and in vivo assays. Starting from the example of the marketed drug NBDNJ (N-butyl deoxynojirimycin), a variety of iminosugars have exhibited the capacity to rescue the trafficking of F508del-CFTR (deletion of F508 residue in the CF transmembrane conductance regulator), either alone or in combination with other correctors. Interesting results have also been obtained when iminosugars were considered as anti-inflammatory agents in CF lung disease. The data herein reported demonstrate that iminosugars hold considerable potential to be applied for both therapeutic purposes.
Subject(s)
Cystic Fibrosis/drug therapy , Heterocyclic Compounds, 1-Ring/therapeutic use , 1-Deoxynojirimycin/analogs & derivatives , 1-Deoxynojirimycin/chemistry , 1-Deoxynojirimycin/therapeutic use , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/therapeutic use , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Glycoside Hydrolases/antagonists & inhibitors , Glycosyltransferases/antagonists & inhibitors , Heterocyclic Compounds, 1-Ring/chemical synthesis , Heterocyclic Compounds, 1-Ring/chemistry , Humans , Imino Pyranoses/chemistry , Imino Pyranoses/therapeutic use , Inflammation , Molecular Structure , Mutation , Sequence Deletion , Tartrates/chemistry , Tartrates/therapeutic useABSTRACT
A series of analogs of the iminosugars 1-deoxynojirimycin (DNJ) and 1-deoxymannojirimycin (DMJ), in which an extra five or six-membered ring has been fused to the C1-C2 bond have been prepared. The synthetic strategy exploits a key 2-keto-C-allyl iminosugar, easily accessible from gluconolactam, which upon Grignard addition and RCM furnishes a bicyclic scaffold that can be further hydroxylated at the C[double bond, length as m-dash]C bond. This strategy furnished DNJ mimics with the piperidine ring locked in a 1C4 conformation with all substituents in axial orientation when fused to a six-membered ring. Addition of an extra ring to DNJ and DMJ motif proved to strongly modify the glycosidase inhibition profile of the parent iminosugars leading to modest inhibitors. The 2-keto-C-allyl iminosugar scaffold was further used to access N-acetylglycosamine analogs via oxime formation.
Subject(s)
1-Deoxynojirimycin/pharmacology , Glycoside Hydrolase Inhibitors/pharmacology , alpha-Glucosidases/metabolism , beta-Glucosidase/antagonists & inhibitors , 1-Deoxynojirimycin/chemical synthesis , 1-Deoxynojirimycin/chemistry , Animals , Cattle , Coffee/enzymology , Dose-Response Relationship, Drug , Glycoside Hydrolase Inhibitors/chemical synthesis , Glycoside Hydrolase Inhibitors/chemistry , Liver/enzymology , Molecular Conformation , Oryza/enzymology , Structure-Activity Relationship , beta-Glucosidase/metabolismABSTRACT
The highly stereocontrolled de novo synthesis of l-NBDNJ (the unnatural enantiomer of the iminosugar drug Miglustat) and a preliminary evaluation of its chaperoning potential are herein reported. l-NBDNJ is able to enhance lysosomal α-glucosidase levels in Pompe disease fibroblasts, either when administered singularly or when coincubated with the recombinant human α-glucosidase. In addition, differently from its d-enantiomer, l-NBDNJ does not act as a glycosidase inhibitor.
Subject(s)
1-Deoxynojirimycin/analogs & derivatives , Enzyme Activation/drug effects , Fibroblasts/drug effects , Glycogen Storage Disease Type II/drug therapy , alpha-Glucosidases/metabolism , 1-Deoxynojirimycin/chemical synthesis , 1-Deoxynojirimycin/chemistry , 1-Deoxynojirimycin/pharmacology , Allosteric Regulation/drug effects , Cell Line , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Fibroblasts/enzymology , Fibroblasts/metabolism , Glycogen Storage Disease Type II/enzymology , Glycogen Storage Disease Type II/metabolism , Humans , Lysosomes/drug effects , Lysosomes/enzymology , Lysosomes/metabolism , Models, Molecular , StereoisomerismABSTRACT
Mulberry leaves have commonly been utilized in China as a herbal medicine for the treatment of diabetes for thousands of years. To evaluate the quality, an ultra-high performance liquid chromatography coupled with quadrupole time of flight mass spectrometry (UPLC-Q-TOF/MS) method was developed for identification of polyhydroxylated alkaloids with α-glucosidase inhibitor activity in mulberry leaf. As a result, five alkaloid compounds were identiï¬ed or tentatively characterized. Among them, the compound 1-deoxynojirimycin (DNJ) was selected as the most typical and active chemical marker and quantiï¬ed using an improved high performance liquid chromatography (HPLC) normal phase coupled with evaporative light scattering detector (ELSD) method. The developed method was fully validated in terms of linearity, sensitivity, precision and repeatability, as well as recovery, and subsequently applied to evaluate twenty-nine batches of mulberry leaves from different collections. From the analytical data it was discovered that the average content of DNJ is 1.53 mg/g, while the total contents of DNJ in the 29 mulberry leaf sample ranged from 0.20 to 3.88 mg/g, which suggested remarkable differences, although it reached the highest levels in early August. These data may provide an important reference for the quality of mulberry leaves used as herbal medicine for the treatment of diabetes or as a material to obtain the DNJ of α-glucosidase inhibitor or as a functional food.
Subject(s)
1-Deoxynojirimycin/isolation & purification , Alkaloids/chemistry , Morus/chemistry , Plant Extracts/analysis , 1-Deoxynojirimycin/chemistry , Alkaloids/pharmacology , Chromatography, High Pressure Liquid/methods , Glycoside Hydrolase Inhibitors/chemistry , Glycoside Hydrolase Inhibitors/pharmacology , Mass Spectrometry/methods , Plant Leaves/chemistryABSTRACT
2-Acetamido-1,2-dideoxyiminosugars are selective and potent inhibitors of hexosaminidases and therefore show high therapeutic potential for the treatment of various diseases, including several lysosomal storage disorders. A stereoselective synthesis of 2-acetamido-1,2-dideoxynojirimycin (DNJNAc), the iminosugar analog of N-acetylglucosamine, with a high overall yield is here described. This novel procedure further allowed accessing ureido-DNJNAc conjugates through derivatization of the endocyclic amine on a key pivotal intermediate. Remarkably, some of the ureido-DNJNAc representatives behaved as potent and selective inhibitors of ß-hexosaminidases, including the human enzyme, being the first examples of neutral sp(2)-iminosugar-type inhibitors reported for these enzymes. Moreover, the amphiphilic character of the new ureido-DNJNAc is expected to confer better drug-like properties.
Subject(s)
1-Deoxynojirimycin/analogs & derivatives , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , beta-N-Acetylhexosaminidases/antagonists & inhibitors , 1-Deoxynojirimycin/chemical synthesis , 1-Deoxynojirimycin/chemistry , 1-Deoxynojirimycin/pharmacology , Acetamides/chemical synthesis , Acetamides/chemistry , Animals , Cattle , Chemistry Techniques, Synthetic , Drug Evaluation, Preclinical/methods , Enzyme Inhibitors/chemical synthesis , Humans , Molecular Structure , Stereoisomerism , Structure-Activity Relationship , beta-N-Acetylhexosaminidases/isolation & purificationABSTRACT
In the present study, the extraction technology and preparative separation of 1-deoxynojirimycin from mulberry leaves were systematically investigated. Four extraction parameters (ethanol concentration, extraction temperature, extraction time and ratio of solvent to sample) were explored by response surface methodology (RSM). The results indicated that the maximal yield of 1-deoxynojirimycin was achieved with an ethanol concentration of 55%, extraction temperature of 80 °C, extraction time of 1.2 h and ratio of solvent to sample of 12:1. The extraction yield under these optimum conditions was found to be 256 mg/100 g dry mulberry leaves. A column packed with a selected resin was used to perform dynamic adsorption and desorption tests to optimize the separation process. The results show that the preparative separation of 1-deoxynojirimycin from mulberry leaves can be easily and effectively done by adopting 732 resin. In conclusion, 732 resin is the most appropriate for the separation of 1-deoxynojirimycin from other components in mulberry leaves extracts, and its adsorption behavior can be described with Langmuir isotherms and a two-step adsorption kinetics model. The recovery and purity of 1-deoxynojirimycin in the final product were 90.51% and 15.3%, respectively.
Subject(s)
1-Deoxynojirimycin/chemistry , Morus/chemistry , Plant Extracts/chemistry , Plant Leaves/chemistry , Resins, Plant/chemistry , 1-Deoxynojirimycin/isolation & purification , Plant Extracts/isolation & purificationABSTRACT
A growing body of evidence suggests that misfolding of a mutant protein followed by its aggregation or premature degradation in the endoplasmic reticulum is one of the main mechanisms that underlie inherited neurodegenerative diseases, including lysosomal storage diseases. Chemical or pharmacological chaperones are small molecules that bind to and stabilize mutant lysosomal enzyme proteins in the endoplasmic reticulum. A number of chaperone compounds for lysosomal hydrolases have been identified in the last decade. They have gained attention because they can be orally administrated, and also because they can penetrate the blood-brain barrier. In this article, we describe two chaperone candidates for the treatment of GM1-gangliosidosis. We also discuss the future direction of this strategy targeting other lysosomal storage diseases as well as protein misfolding diseases in general.
Subject(s)
1-Deoxynojirimycin/analogs & derivatives , Gangliosidosis, GM1/drug therapy , Hexosamines/pharmacology , Lysosomes/enzymology , Small Molecule Libraries/pharmacology , beta-Galactosidase/genetics , 1-Deoxynojirimycin/chemistry , 1-Deoxynojirimycin/pharmacology , Animals , Gangliosidosis, GM1/enzymology , Gangliosidosis, GM1/genetics , Genotype , Hexosamines/chemistry , Humans , Lysosomes/drug effects , Lysosomes/genetics , Mutation , Small Molecule Libraries/chemistryABSTRACT
Acquired immune deficiency syndrome (AIDS) is a severe infectious disease that causes a large number of deaths every year. Traditional anti-AIDS drugs directly targeting the HIV-1 encoded enzymes including reverse transcriptase (RT), protease (PR) and integrase (IN) usually suffer from drug resistance after a period of treatment and serious side effects. In recent years, the emergence of numerous useful information of protein-protein interactions (PPI) in the HIV life cycle and related inhibitors makes PPI a new way for antiviral drug intervention. In this study, we identified 26 core human proteins involved in PPI between HIV-1 and host, that have great potential for HIV therapy. In addition, 280 chemicals that interact with three HIV drugs targeting human proteins can also interact with these 26 core proteins. All these indicate that our method as presented in this paper is quite promising. The method may become a useful tool, or at least plays a complementary role to the existing method, for identifying novel anti-HIV drugs.
Subject(s)
Algorithms , Anti-HIV Agents/chemistry , HIV Infections/drug therapy , HIV-1/drug effects , Protein Interaction Mapping , Protein Interaction Maps , 1-Deoxynojirimycin/analogs & derivatives , 1-Deoxynojirimycin/chemistry , 1-Deoxynojirimycin/pharmacology , Anti-HIV Agents/pharmacology , CCR5 Receptor Antagonists , Computer Simulation , Cyclohexanes/chemistry , Cyclohexanes/pharmacology , Databases, Chemical , Didanosine/chemistry , Didanosine/pharmacology , Drug Design , Drug Discovery , HIV Infections/virology , HIV-1/genetics , HIV-1/metabolism , Host-Pathogen Interactions , Humans , Maraviroc , Models, Molecular , Receptors, CCR5/chemistry , Receptors, CCR5/metabolism , Triazoles/chemistry , Triazoles/pharmacologyABSTRACT
Novel N-alkyldeoxynojirimycins (NADNJs) with two hydrophobic groups attached to a nitrogen linker on the alkyl chain were designed. A novel NADNJ containing a terminal tertiary carboxamide moiety was discovered that was a potent inhibitor against BVDV. Further optimization resulted in a structurally more stable lead compound 24 with a submicromolar EC50 against BVDV, Dengue, and Tacaribe; and low cytotoxicity.
Subject(s)
Amides/pharmacology , Antiviral Agents/pharmacology , Defective Viruses/drug effects , Dengue/drug therapy , Diarrhea Viruses, Bovine Viral/drug effects , Glucosamine/analogs & derivatives , 1-Deoxynojirimycin/chemical synthesis , 1-Deoxynojirimycin/chemistry , 1-Deoxynojirimycin/pharmacology , Amides/chemical synthesis , Amides/chemistry , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Cell Line , Cell Survival/drug effects , Cricetinae , Dose-Response Relationship, Drug , Glucosamine/chemical synthesis , Glucosamine/chemistry , Glucosamine/pharmacology , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
A viable treatment for lysosomal storage disease has been very difficult to attain. One option is pharmacological inhibition of synthetic pathways to reduce substrate accumulations. Miglustat N-butyldeoxynojirimycin (NBDNJ), an inhibitor of glucosylceramide synthase, has shown much promise in clinical trials for the treatment of Type I Gaucher disease. The molecular events invoked by NBDNJ in cell culture and in animal models have not been so definitive. This review discusses the biochemical and molecular impact of NBDNJ as it relates to its potential as a therapeutic drug.
Subject(s)
1-Deoxynojirimycin/analogs & derivatives , Gaucher Disease/drug therapy , 1-Deoxynojirimycin/chemistry , 1-Deoxynojirimycin/therapeutic use , Animals , Clinical Trials as Topic , Disease Models, Animal , Gangliosides/biosynthesis , Gangliosides/chemistry , HumansABSTRACT
Mulberry 1-deoxynojirimycin (DNJ), a potent α-glycosidase inhibitor, has therapeutic potency in the suppression of postprandial blood glucose levels thereby possibly preventing diabetes mellitus. However, DNJ has a relatively short half-life in vivo (about 2 h). Therefore, several doses of mulberry DNJ are required to achieve optimal therapeutic results. This study aimed to delay the release of mulberry DNJ with biodegradable matrices to maintain the intestinal DNJ concentration and prolong the hypoglycaemic effect in vivo. A novel, simple, and commercially viable method was adopted to develop DNJ-entrapped microspheres (DNJ-MSs). A higher extent of crosslinking and the larger sized DNJ-MS decreased the rate of mulberry DNJ release in vitro. Consequently, an in vivo study was performed in Wistar rats over a 6 h period. The area under curve (AUC) of rats with DNJ-MS was significantly increased, compared to animals dosed with mulberry powder (control). DNJ-MS suppressed postprandial glucose from sucrose administration at the initial and 3 h time points indicating a prolonged hypoglycaemic effect.
Subject(s)
1-Deoxynojirimycin/chemistry , Chemistry, Pharmaceutical/methods , Delayed-Action Preparations/chemistry , Gelatin/chemistry , Hypoglycemic Agents/chemistry , Morus/chemistry , Plant Extracts/chemistry , 1-Deoxynojirimycin/pharmacokinetics , Animals , Delayed-Action Preparations/pharmacokinetics , Female , Fruit/chemistry , Humans , Hypoglycemic Agents/pharmacokinetics , Kinetics , Male , Plant Extracts/pharmacokinetics , Rats , Rats, Wistar , Skin/chemistry , SwineABSTRACT
Gaucher disease (GD) is a disorder of glycosphingolipid metabolism caused by deficiency of lysosomal glucocerebrosidase (GlcCerase) activity, due to conformationally or functionally defective variants, resulting in progressive deposition of glycosylceramide in macrophages. The glucose analogue, N-butyldeoxynojirimycin (NB-DNJ, miglustat), is an inhibitor of the ceramide-specific glycosyltransferase, which catalyzes the first step of glycosphingolipid biosynthesis and is currently approved for the oral treatment of type 1 GD. In a previous work, we found a GlcCerase activity increase in cell cultures in the presence of NB-DNJ, which could imply that this compound is not only a substrate reducer but also a pharmacological chaperone or inhibitor for GlcCerase degradation. In this work we compare imiglucerase (the enzyme currently used for replacement therapy) and velaglucerase alfa (a novel therapeutic enzyme form) in terms of conformational stability and enzymatic activity, as well as the effect of NB-DNJ on them. The interaction between these enzymes and NB-DNJ was studied by isothermal titration calorimetry. Our results reveal that, although velaglucerase alfa and imiglucerase exhibit very similar activity profiles, velaglucerase alfa shows higher in vitro thermal stability and is less prone to aggregation/precipitation, which could be advantageous for storage and clinical administration. In addition, we show that at neutral pH NB-DNJ binds to and enhances the stability of both enzymes, while at mildly acidic lysosomal conditions it does not bind to them. These results support the potential role of NB-DNJ as a pharmacological chaperone, susceptible of being part of pharmaceutical formulation or combination therapy for GD in the future.
Subject(s)
1-Deoxynojirimycin/analogs & derivatives , Gaucher Disease , Glucosylceramidase/chemistry , Glucosylceramidase/metabolism , Molecular Chaperones , 1-Deoxynojirimycin/chemistry , Calorimetry, Differential Scanning , Drug Stability , Enzyme Stability , Gaucher Disease/therapy , Humans , Hydrogen-Ion Concentration , Models, Biological , Molecular Chaperones/chemistry , Molecular Chaperones/metabolism , TemperatureABSTRACT
For the purpose of this article, iminosugars are polyhydroxylated secondary and tertiary amines in which the molecules resemble monosaccharide sugars in which the ring oxygen is replaced by the nitrogen. The bicyclic structures may biologically resemble disaccharides. Very few iminosugars have been available up to now for evaluation of their pharmaceutical applications. The early compounds were discovered and selected for study due to glycosidase inhibition, which is now known to not be necessary for pharmacological activity and may cause off-target effects. Glyset® and Zavesca®, derived from the glucosidase-inhibiting natural product 1-deoxynojirimycin, are the first two examples of iminosugar drugs. Since the discovery of this first generation, many new natural products have been identified with a wide range of biological activities but few are widely available. Among the biological properties of these compounds are good oral bioavailability and very specific immune modulatory and chaperoning activity. Although the natural products from plants and microorganisms can have good specificity, modifications of the template natural products have been very successful recently in producing bioactive compounds with good profiles. The field of iminosugars continues to open up exciting new opportunities for therapeutic agent discovery and offers many new tools for precisely modifying carbohydrate structures and modulating glycosidase activity in vivo. Current efforts are directed towards a greater range of structures and a wider range of biochemical targets.
Subject(s)
Imino Sugars/chemistry , 1-Deoxynojirimycin/chemistry , 1-Deoxynojirimycin/pharmacology , 1-Deoxynojirimycin/therapeutic use , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Gaucher Disease/drug therapy , Glycoside Hydrolases/antagonists & inhibitors , Glycoside Hydrolases/metabolism , Humans , Hyperglycemia/drug therapy , Imino Sugars/pharmacology , Imino Sugars/therapeutic use , Molecular Chaperones/chemistry , Molecular Chaperones/metabolism , Virus Diseases/drug therapyABSTRACT
We here describe a simple and efficient synthetic method for a non-hydrolysable precursor of a GDP-fucose analogue: The synthesis of the racemic aminofuranofucitol 3 from sorbic alcohol by nitroso-Diels-Alder reaction. This 'all-cis-pyrrolidine', with all substituents occupying a cis position, has been determined as a potent inhibitor of α-L-fucosidase and a moderate inhibitor of α- and ß-D-galactosidase. The good recognition of this fucose moiety analogue by specific enzymes is thus confirmed. The C-anomeric bond in this particular structure is in the ß-position and makes this compound an interesting candidate for further chemical modifications. Influence of the methyl and hydroxymethyl groups on the inhibition potency is discussed.
Subject(s)
1-Deoxynojirimycin/analogs & derivatives , Enzyme Inhibitors/chemical synthesis , Galactosidases/antagonists & inhibitors , Pyrrolidines/chemistry , Sugar Alcohols/chemical synthesis , alpha-L-Fucosidase/antagonists & inhibitors , 1-Deoxynojirimycin/chemical synthesis , 1-Deoxynojirimycin/chemistry , 1-Deoxynojirimycin/pharmacology , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Galactosidases/metabolism , Isomerism , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacology , Sugar Alcohols/chemistry , Sugar Alcohols/pharmacology , alpha-L-Fucosidase/metabolismABSTRACT
1-Deoxynojirimycin (DNJ) occurs in mulberry and other plants and is a highly potent glycosidase inhibitor reported to suppress blood glucose levels, thus preventing diabetes. Derivatization is required for quantification of DNJ upon use of spectral detection methods. Because of this difficulty, the DNJ contents of mulberry-based food products are rarely stated, even if DNJ is their active component. A simple, selective, and rapid method of high-performance anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD) to quantify DNJ in mulberry-based food products was developed. Stability testing of DNJ under heat treatment was also performed. A water extract of mulberry tea sample was subjected to HPAEC-PAD in a CarboPac MA1 column with a sodium hydroxide gradient. DNJ was clearly separated at a retention time of 7.26 min without interference and was selectively detected in the water extract. The detection limit was 5 ng. Heat stability studies suggested that DNJ was heat stable. HPAEC-PAD was not subject to interference, was highly selective for DNJ, and was superior to other high-performance liquid chromatography (HPLC) techniques in terms of sample preparation, resolution, and sensitivity. The method allowed simple, selective, and rapid analysis of DNJ in food matrices and might be useful for development of mulberry-based food products. Heat treatment could be an option for sterilizing mulberry-based products.
Subject(s)
1-Deoxynojirimycin/analysis , Food Analysis/methods , Morus/chemistry , Plant Leaves/chemistry , 1-Deoxynojirimycin/chemistry , 1-Deoxynojirimycin/isolation & purification , Beverages/analysis , Chromatography, High Pressure Liquid , Chromatography, Ion Exchange/methods , Dietary Supplements/analysis , Electrochemical Techniques , Fast Foods/analysis , Hot Temperature/adverse effects , Hydrogen-Ion Concentration , Limit of Detection , Mass Spectrometry , Time FactorsABSTRACT
OBJECTIVE: To study the chemical constituents from the leaves of Morus multicaulis. METHOD: The compounds were isolated by ion exchange resin, silica gel and Sephadex LH -20 column chromatographies. Their structures were elucidated on the basis of physico-chemical properties and spectral data. RESULT: Twelve compounds were isolated from the leaves of this plant. Their structures were identified as 1-deoxynojirimycin (1), fagomine (2), 2-O-alpha-D-galactopyranosyl-1-deoxynojirimycin (3), quercetin-7-O-beta-D-glucoside (4), kaempferol (5), quercetin (6), scopoletin (7), D-aspartic acid (8), L-proline (9), D-alpha-alanine (10), myo-inositol (11) and dausterol (12). CONCLUSION: All compounds were isolated from this plant for the first time.