Search Results (60)

Deoxynojirimycin (DNJ), the first isolated iminosugar, is a natural alkaloid acting as a potent inhibitor of α-glucosidase with high nutritional value. It naturally occurs in plants (especially Morus spp.), microbes, and insects or can be synthesized. Diverse biological activities, such as antihyperglycemic, lipid-lowering, antitumor, antiviral, and anti-inflammatory, have been recognized for this compound. However, DNJ has not been approved as a food supplement until now. Several studies, also in clinics, are carried out on Morus spp. containing DNJ. Among Morus spp., Morus alba L. (white mulberry), Morus nigra L. (black mulberry), and Morus rubra L. (red mulberry) are the three main species that grow all over the world. Some spurious studies have been conducted on Reducose^® and Glubloc™, two products that contain DNJ and Morus alba, respectively. However, mulberry allergy, including respiratory allergy, airborne contact urticaria, anaphylaxis, oral allergy syndrome, and food induced urticaria, may be observed. This review aims to explore a crucial and timely question: how DNJ exerts its biological effects and what role it may play in therapeutic applications. We provide a comprehensive summary of the current understanding of DNJ’s pharmacological potential and the methods used for its production. We also report recent developments in clinical studies on Morus alba, Reducose^® and Glubloc™. Full article

Amorpha fruticosa L. (Fabaceae) originates from North America and has become an aggressive invasive plant in many parts of the world. It affects the local biodiversity in many negative ways. Our previous in vivo tests of purified extract of A. fruticosa pods for antihyperglycemic activity in streptozotocin-induced diabetic spontaneously hypertensive rats (SHRs) revealed that the oral administration of purified extract of A. fruticosa (100 mg/kg) for 35 days to SHRs caused significant decreases in the systolic pressure, blood glucose levels, and MDA quantity. The aim of this experimental study is to test the glycosidase inhibition of several extracts of A. fruticosa pods. Methods: GC-MS, NMR, and a glycosidase inhibition assay were performed. Results: The results demonstrate strong inhibition of yeast alpha- and almond beta-glucosidases, rat intestinal hexosaminidase, and bovine beta-glucuronidase, but not of some other glycosidases. The activity is probably due at least in part to the presence of iminosugars and iminosugar acids. We here report on further analysis and activity assessments of A. fruticosa pods and leaves collected in Bulgaria, and for the first time discover glycosidase inhibitors, pinitol, and hydroxylated pipecolic acids in the species and more complex iminosugar-like compounds that may all contribute to antidiabetic potential. Hydroxylated pipecolic acids are probable precursors of iminosugars and common in legumes containing them. Considerable chemical variation was observed over four pod collections. Conclusions: A. fruticosa pods and leaves were found to contain a number of compounds that could contribute to the potential antihyperglycemic activities including pinitol and a complex mixture of iminosugar-related compounds derived from pipecolic acids and prolines. The pods and leaves caused potent selective inhibition of glucosidases and hexosaminidases and beta-glucuronidase. The variation between the collections might reflect the sites differing or wide phenotypic versatility allowing the success of the species as an invasive plant. Full article

Background: Iminosugars are natural or synthetic sugar analogues with a very broad spectrum of activities, including those against the most prominent bacterial pathogens, like P. aeruginosa or S. aureus. In a series of studies, we have demonstrated that one of the synthetic iminosugars, PDIA (beta-1-C-propyl-1,4-dideoxy-1,4-imino-L-arabinitol), possesses the ability to suppress biofilm production by different pathogenic bacteria without inhibiting their growth. Thereby, PDIA is able to influence experimental skin infection caused by S. aureus. Methods: To elucidate molecular mechanisms by which PDIA impedes biofilm formation by S. aureus, a transcriptomic study was performed in which a biofilm-producing S. aureus strain was grown in the presence of PDIA for 24 and 48 h in comparison to a control without the iminosugar. The RNA was then isolated, converted into cDNA, sequenced, and data analysis was performed. Results: It appeared that PDIA caused the down-regulation of many bacteriophage genes responsible for the processes of bacterial cell lysis, and some genes responsible for cell wall degradation were also down-regulated. Among the 25 most upregulated genes were those representing the phosphotransferase system (PTS), which is required for carbohydrate uptake and control of carbon metabolism. The ranking of the most significant down-regulated genes after 24 h exposure to PDIA shows that they predominantly coded for both the synthesis and lysis of the peptidoglycan. Conclusions: We have shown here that the influence of PDIA on the expression of S. aureus genes is broad and affects many genes encoding metabolism and ribosomes. Full article

Morquio A syndrome is a lysosomal disorder caused by the deficiency of the lysosomal enzyme N-acetylgalactosamine 6-sulfatase (GALNS, EC 3.1.6.4). Currently, enzyme replacement therapy (ERT) is used to treat Morquio A through the infusion of the recombinant enzyme VIMIZIM^® (elosulfase alfa, BioMarin). Unfortunately, the recombinant enzyme exhibits low conformational stability in vivo. A promising approach to address this issue is the coadministration of recombinant human GALNS (rhGALNS) with a pharmacological chaperone (PC), a molecule that selectively binds to the misfolded protein, stabilizes its conformation, and assists in the restoration of the impaired function. We report in this work the synthesis of a library of multivalent glycomimetics exploiting the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction between several dendrimeric scaffolds armed with terminal alkynes and azido ending iminosugars of different structures (pyrrolidines, piperidines, and pyrrolizidines) or simple azido ending carbohydrates as bioactive units. The biological evaluation identified pyrrolidine-based nonavalent dendrimers 1 and 36 as the most promising compounds, able both to bind the native enzyme with IC₅₀ in the micromolar range and to act as enzyme stabilizers toward rhGALNS in a thermal denaturation study, thus identifying promising compounds for a combined PC/ERT therapy. Full article

Iminosugars have a carbohydrate-like backbone in which the ring oxygen is replaced by nitrogen. They are naturally found in foods such as rice, buckwheat, mulberries, and fermented vegetables, and are reported to exert anti-hyperlipidemic and anti-hyperglycemic effects due to the inhibition of cellular glycosidases. This mechanism suggests their potential role in cancer treatment and prevention. In this study, two natural iminosugars, D-fagomine (FGM) and 1-deoxynojirimycin (DNJ), and their synthetic derivatives were screened for potential anticancer properties using Caco-2 and HCT-116 cells as models for the early and late stages of colon cancer, respectively. Iminosugars were found to decrease cell viability, with effects varying based on the type of iminosugar, cell type, growth condition (glucose concentration), exposure time (1 vs. 13 days), and tissue architecture (monolayer vs. spheroid). The combined use of innovative techniques, such as IncuCyte^® live cell imaging and Seahorse real-time cellular metabolic analysis, and microscopic observation after staining enabled us to detect changes in substrate utilization for energy metabolism, including increased glycolysis and alterations in lipid and glycogen stores. The evidence that iminosugars, both natural and synthetic, influence cellular bioenergetics paves the way for their potential use in various applications, including cancer treatment. Full article

Given the crucial roles of carbohydrates in energy supply, biochemical processes, signaling events and the pathogenesis of several diseases, the development of carbohydrate analogues, called glycomimetics, is a key research area in Glycobiology, Pharmacology, and Medicinal Chemistry. Among the many structural transformations explored, the replacement of endo- and exocyclic oxygen atoms by carbon (carbasugars) or heteroatoms, such as nitrogen (aza- and iminosugars), phosphorous (phosphasugars), sulfur (thiosugars), selenium (selenosugars) or tellurium (tellurosugars) have garnered significant attention. These isosteric substitutions can modulate the carbohydrate bioavailability, stability, and bioactivity, while introducing new properties, such as redox activity, interactions with pathological lectins and enzymes, or cytotoxic effects. In this manuscript we have focused on three major families of glycomimetics: thio-, seleno-, and tellurosugars. We provide a comprehensive review of the most relevant synthetic pathways leading to substitutions primarily at the endocyclic and glycosidic positions. The scope includes metal-catalyzed reactions, organocatalysis, electro- and photochemical transformations, free-radical processes, and automated syntheses. Additionally, mechanistic insights, stereoselectivity, and biological properties are also discussed. The structural diversity and promising bioactivities of these glycomimetics underscore their significance in this research area. Full article

This paper describes the first detailed NMR analysis of the borylated intermediates and target compounds for a small library of pyrrolidine iminosugars of l-gulose absolute stereochemical configuration. The iminosugars were functionalised via N-alkylation to bear a boronate ester or boronic acid groups. The addition of the organic boron pharmacophore allows to further explore the chemical space around and in the active sites, where the boron atom has the capability to make reversible covalent bonds with enzyme nucleophiles and other nucleophiles. We discuss the concurrent complex equilibrium processes of mutarotation and borarotation as studied by NMR. Full article

A straightforward synthetic route towards DAB-1 scaffolded dimeric iminosugars is described here, starting from readily available bis-glycosylamines. The method allows the integration of a variety of linkages (aryl, alkyl, polyethyleneglycol chains) between both iminosugars through the choice of the bis-amine used in the first step. Moreover, an additional substituent (allyl, ethynyl) may be inserted into the structure via nucleophilic addition of an organometallic reagent to the starting bis-glycosylamine. A symmetrical ethynyl-iminosugar proved susceptible to intramolecular Glaser coupling, affording the corresponding macrocyclic structure. Dimeric iminosugars were tested towards a series of commercial glycosidases to uncover potencies and selectivities when compared to DAB-1, their monomeric counterpart. Whereas a significant drop in inhibition potencies was observed towards glucosidases, some compounds displayed unexpected potent inhibition of β-galactosidase. Full article

An efficient and convenient strategy has been successfully developed for the preparation of novel hydroxylated alkaloid derivatives (also called fused multicyclic iminosugars) from p-toluenesulfonylated sugars through a Pictet–Spengler-type mechanism. This method is highly stereoselective, does not require metal catalysts, and capable of conducting gram level reactions (with a 53% yield). Some of such iminosugars had an intermediate antiproliferative effect on HCT116 tumor cells. Full article

Bacteria are capable of remarkable adaptations to their environment, including undesirable bacterial resistance to antibacterial agents. One of the most serious cases is an infection caused by multidrug-resistant Staphylococcus aureus, which has unfortunately also spread outside hospitals. Therefore, the development of new effective antibacterial agents is extremely important to solve the increasing problem of bacterial resistance. The bacteriolytic enzyme autolysin E (AtlE) is a promising new drug target as it plays a key role in the degradation of peptidoglycan in the bacterial cell wall. Consequently, disruption of function can have an immense impact on bacterial growth and survival. An in silico and in vitro evaluation of iminosugar derivatives as potent inhibitors of S. aureus (AtlE) was performed. Three promising hit compounds (1, 3 and 8) were identified as AtlE binders in the micromolar range as measured by surface plasmon resonance. The most potent compound among the SPR response curve hits was 1, with a K_D of 19 μM. The K_D value for compound 8 was 88 μM, while compound 3 had a K_D value of 410 μM. Full article

Inhibition of glycoside hydrolases has widespread application in the treatment of diabetes. Based on our previous findings, a series of dihydrofuro[3,2-b]piperidine derivatives was designed and synthesized from D- and L-arabinose. Compounds 32 (IC₅₀ = 0.07 μM) and 28 (IC₅₀ = 0.5 μM) showed significantly stronger inhibitory potency against α-glucosidase than positive control acarbose. The study of the structure–activity relationship of these compounds provides a new clue for the development of new α-glucosidase inhibitors. Full article

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. Full article

Gaucher disease (GD) is a rare genetic metabolic disorder characterized by a dysfunction of the lysosomal glycoside hydrolase glucocerebrosidase (GCase) due to mutations in the gene GBA1, leading to the cellular accumulation of glucosylceramide (GlcCer). While most of the current research focuses on the primary accumulated material, lesser attention has been paid to secondary storage materials and their reciprocal intertwining. By using a novel approach based on flow cytometry and fluorescent labelling, we monitored changes in storage materials directly in fibroblasts derived from GD patients carrying N370S/RecNcil and homozygous L444P or R131C mutations with respect to wild type. In L444P and R131C fibroblasts, we detected not only the primary accumulation of GlcCer accumulation but also a considerable secondary increase in GM1 storage, comparable with the one observed in infantile patients affected by GM1 gangliosidosis. In addition, the ability of a trivalent trihydroxypiperidine iminosugar compound (CV82), which previously showed good pharmacological chaperone activity on GCase enzyme, to reduce the levels of storage materials in L444P and R131C fibroblasts was tested. Interestingly, treatment with different concentrations of CV82 led to a significant reduction in GM1 accumulation only in L444P fibroblasts, without significantly affecting GlcCer levels. The compound CV82 was selective against the GCase enzyme with respect to the β-Galactosidase enzyme, which was responsible for the catabolism of GM1 ganglioside. The reduction in GM1-ganglioside level cannot be therefore ascribed to a direct action of CV82 on β-Galactosidase enzyme, suggesting that GM1 decrease is rather related to other unknown mechanisms that follow the direct action of CV82 on GCase. In conclusion, this work indicates that the tracking of secondary storages can represent a key step for a better understanding of the pathways involved in the severity of GD, also underlying the importance of developing drugs able to reduce both primary and secondary storage-material accumulations in GD. Full article

The nicotinamide phosphoribosyltransferase (NAMPT) is considered a very promising therapeutic target because it is overexpressed in pancreatic cancer. Although many inhibitors have been prepared and tested, clinical trials have shown that NAMPT inhibition may result in severe haematological toxicity. Therefore, the development of conceptually new inhibitors is an important and challenging task. We synthesized ten β-d-iminoribofuranosides bearing various heterocycle-based chains carbon-linked to the anomeric position starting from non-carbohydrate derivatives. They were then submitted to NAMPT inhibition assays, as well as to pancreatic tumor cells viability and intracellular NAD⁺ depletion evaluation. The biological activity of the compounds was compared to that of the corresponding analogues lacking the carbohydrate unit to assess, for the first time, the contribution of the iminosugar moiety to the properties of these potential antitumor agents. Full article

Crimean-Congo haemorrhagic fever virus (CCHFV) is a pathogen of increasing public health concern, being a widely distributed arbovirus and the causative agent of the potentially fatal Crimean-Congo haemorrhagic fever. Hazara virus (HAZV) is a genetically and serologically related virus that has been proposed as a surrogate for antiviral and vaccine testing for CCHFV. Glycosylation analysis of HAZV has been limited; first, we confirmed for the first time the occupation of two N-glycosylation sites in the HAZV glycoprotein. Despite this, there was no apparent antiviral efficacy of a panel of iminosugars against HAZV, as determined by quantification of the total secretion and infectious virus titres produced following infection of SW13 and Vero cells. This lack of efficacy was not due to an inability of deoxynojirimycin (DNJ)-derivative iminosugars to access and inhibit endoplasmic reticulum α-glucosidases, as demonstrated by free oligosaccharide analysis in uninfected and infected SW13 and uninfected Vero cells. Even so, iminosugars may yet have potential as antivirals for CCHFV since the positions and importance of N-linked glycans may differ between the viruses, a hypothesis requiring further evaluation. Full article