Search

We achieved synthesis of seven stereoisomers of 1- C-n- butyl-L-iminofuranose derivatives using catalytic asymmetric alkylation and Negishi coupling as key reactions. The synthetic strategy based on these key reactions was quite useful, since both α- and β-iminofuranoses could be obtained by switching the chirality of the ligand employed for the AAA reaction. The common intermediates for α- and β-isomers were subjected to further manipulations to install a diol unit at C2 and C3 to give the desired stereoisomers of L-iminofuranose derivatives. We achieved the preparation of all stereoisomers of 1- C-n- butyl-L-iminofuranose derivatives, with the exception of β-lyxo type iminofuranose. It is noteworthy that a synthetic route for many stereoisomers of iminofuranose derivatives was developed. Unfortunately, none of the L-iminofuranoses obtained showed inhibitory activity against the α-glycosidases examined—e.g., maltase, sucrase, and isomaltase. Image 1 [ABSTRACT FROM AUTHOR]

Abstract Glycolipid mimetics consisting of a bicyclic polyhydroxypiperidine-cyclic carbamate core and a pseudoanomeric hydrophobic tail, termed sp2-iminosugar glycolipids (sp2-IGLs), target microglia during neuroinflammatory processes. Here we have synthesized and investigated new variants of sp2-IGLs for their ability to suppress the activation of human monocyte-derived dendritic cells (DCs) by lipopolysaccharide (LPS) signaling through Toll-like receptor 4. We report that the best lead was (1 R)-1-dodecylsulfonyl-5 N ,6 O -oxomethylidenenojirimycin (DSO 2 -ONJ), able to inhibit LPS-induced TNFα production and maturation of DCs. Immunovisualization experiments, using a mannoside glycolipid conjugate (MGC) that also suppress LPS-mediated DC activation as control, evidenced a distinct mode of action for the sp2-IGLs: unlike MGCs, DSO 2 -ONJ did not elicit internalization of the LPS co-receptor CD14 or induce its co-localization with the Toll-like receptor 4. In a mouse model of LPS-induced acute inflammation, DSO 2 -ONJ demonstrated anti-inflammatory activity by inhibiting the production of the pro-inflammatory interleukin-6. The ensemble of the data highlights sp2-IGLs as a promising new class of molecules against inflammation by interfering in Toll-like receptor intracellular signaling. Graphical abstract Image 1 Highlights • sp2-Iminosugar glycolipids (sp2-IGLs) with S-linked aglycones have been synthesized. • The configuration modulates the antiinflammatory response in LPS-activated human DCs. • sp2-IGLs interfere with TLR-4 intracellular signaling, likely by binding to p38α MAPK. • The best candidate proved efficacy in an in vivo model of LPS-mediated inflammation. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Synthesis of N -alkylated 1-deoxyfuconojirimycins as α-fucosidase inhibitors. • N -Decyl-1-deoxyfuconojirimycin was toxic towards various cancer cells. • Development of homology models for fucosidases from bovine and human origin. Abstract 1,5-Dideoxy-1,5-imino- l -fucitol (1-deoxyfuconojirimycin, DFJ) is an iminosugar that inhibits fucosidases. Herein, N -alkyl DFJs have been synthesised and tested against the α-fucosidases of T. maritima (bacterial origin) and B. taurus (bovine origin). The N -alkyl derivatives were inactive against the bacterial fucosidase, while inhibiting the bovine enzyme. Docking of inhibitors to homology models, generated for the bovine and human fucosidases, was carried out. N -Decyl-DFJ was toxic to cancer cell lines and was more potent than the other N -alkyl DFJs studied. [ABSTRACT FROM AUTHOR]

Abstract The Lewis acid-catalyzed nucleophilic opening of a D- gluco -configured bicyclic hemiaminal has been examined. Several Lewis acids and silylated nucleophiles have been screened allowing the introduction of acetophenone, phosphonate or nitrile at the pseudoanomeric position in satisfactory yields and high 1,2 trans stereoselectivities. Their skeletal rearrangement triggered by the N -benzyl anchimeric assistance provided the corresponding L- ido -configured piperidines displaying various functional groups at C-6 position in good yield. Graphical abstract Image 1 Highlights • Lewis acid-catalyzed nucleophilic opening of a D- gluco -configured bicyclic hemiaminal. • Ring contraction of the resulting azepane functionalized at C-1. • Access to L-idonojirimycin derivatives with orthogonal functions at C-1 and C-6. [ABSTRACT FROM AUTHOR]

Capitalizing on a previously developed Staudinger/azaWittig/Grignard (SAWG)-ring contraction sequence that furnished protected six-membered L-iminosugar C,C -glycosides bearing an allyl group and various substituents at the pseudoanomeric position, the synthesis and glycosidase inhibition of a small library of six- and seven-membered L-iminosugar C,C -glycosides is reported. Their hydrogenolysis or cyclization by RCM followed by deprotection afforded eleven L-iminosugars including spirocyclic derivatives. All compounds adopt a 1C 4 conformation in solution according to NMR data. Compared to previously reported branched L-iminosugars, the L-iminosugar C,C -glycosides reported herein were less potent glycosidase inhibitors. However, some of these compounds showed micromolar inhibition of human lysosome β-glucocerebrosidase suggesting that such iminosugars could be useful to access potent CGase inhibitors by adjusting the structure/length of the pseudoanomeric substituents. [Display omitted] • First biological evaluation of L-iminosugar C,C -glycosideson glycosidases including lysosomal enzymes. • First synthesis of a seven-membered L-iminosugar C,C -glycoside bearing a spirocycle at the pseudoanomeric position. • The six-membered L-iminosugar C,C -glycosides adopt a 1 C 4 conformation according to NMR data. [ABSTRACT FROM AUTHOR]

Stereoselective and biocatalysed synthetic routes to 3,4,5‐trihydroxypiperidines and their N‐ and O‐derivatisations are reviewed. These iminosugars effectively modulate glycosidase enzymes and display biological activities in immunosuppression, as anti‐inflammatory agents and as anti‐viral agents. Syntheses to these building blocks and their N‐ and O‐derivatives are predicted to produce drug leads of high Fsp3 index. This is also crucial in the collection of structure‐activity relationship data, particularly for diseases dependant on glycosidase modulation. Synthetic routes to 3,4,5‐trihydroxypiperidines via stereoselective and biocatalytic protocols, and strategies to their N‐ and O‐derivatisation are reviewed here. 3,4,5‐Trihydroxypiperidines are high Fsp3 index drug leads belonging to the iminosugar family and displaying biological activitites principally as glycosidase modulators. [ABSTRACT FROM AUTHOR]

3,4,5‐Trihydroxypiperidines represent a family of biologically active natural products, found to modulate principally the glycosidase enzymes. This is ascribed to their structural and electronic resemblance to the pyranose monosaccharides, their natural counterparts. Expedient syntheses are crucial to access these valuable high Fsp3 index drug leads. In this review we present the literature strategies to this class of iminosugars to spur further research into drug leads targeting the glycobiological machinery of living systems. 3,4,5‐Trihydroxypiperidines, their derivatives and analogues are biologically active principally as glycosidase modulators. Expedient syntheses are crucial to access these high Fsp3 index drug leads. Syntheses from the chiral pool are reviewed here and their role as drug leads. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • d -Fagomine modifies the gut microbiota composition in Wistar Kyoto rats over a period of 24 weeks. • d -Fagomine promotes diversity of gut microbiota by increasing the Bacteroidetes:Firmicutes ratio over time. • d -Fagomine partially counteracts the loss of Lactobacilliales and Bifidobacteriales over time. • d -Fagomine reduces the levels of excreted short-chain fatty acids. Abstract Diversity and balance of gut microorganisms is fundamental for health throughout life. The aim of this study is to explore the possible eubiotic effect of the buckwheat iminosugar d -fagomine (0.096% w/w in standard feed) in growing healthy Wistar Kyoto rats. Feed and energy intake, residual energy in feces, and body weight gain were independent of d -fagomine supplementation throughout the intervention (24 weeks). The populations of significant bacterial subgroups and species were determined in fecal and cecal DNA by quantitative real-time PCR. d -Fagomine increased the Bacteroidetes:Firmicutes ratio and partially counteracted the loss of Lactobacilliales and Bifidobacteriales over time. The supplementation reduced the levels of excreted short-chain fatty acids (SCFAs) as determined by gas chromatography. This paper provides preliminary evidence that d -fagomine has the capacity to promote microbial functional diversity by increasing the Bacteroidetes:Firmicutes ratio and to mitigate the age-related reduction in populations of the putatively beneficial Lactobacilliales and Bifidobacteriales. [ABSTRACT FROM AUTHOR]

Described here is the asymmetric synthesis of iminosugar 2b , a Lipid II analog, designed to mimic the transition state of transglycosylation catalyzed by the bacterial transglycosylase. The high density of functional groups, together with a rich stereochemistry, represents an extraordinary challenge for chemical synthesis. The key 2,6-anti- stereochemistry of the iminosugar ring was established through an iridium-catalyzed asymmetric allylic amination. The developed synthetic route is suitable for the synthesis of focused libraries to enable the structure–activity relationship study and late-stage modification of iminosugar scaffold with variable lipid, peptide and sugar substituents. Compound 2b showed 70% inhibition of transglycosylase from Acinetobacter baumannii , providing a basis for further improvement. [ABSTRACT FROM AUTHOR]

Synthetic analogues of the naturally occurring iminosugar homoDMDP, which feature a perfluoroalkyl group at the pseudo-anomeric position, have been synthesized from the corresponding sugar-derived cyclic aldonitrone. The new fluorinated iminosugars as well as homoDMDP and its 6-deoxy counterpart were evaluated for their inhibitory activity against a panel of glycosidases. While the replacement of the (1′,2′)-dihydroxyethyl substituent of homoDMDP with –C 4 F 9 proved detrimental for enzyme binding, introduction of a –C 3 F 7 moiety tuned the inhibitory activity spectrum selectively towards α-fucosidase and α-glucosidase from yeast. [ABSTRACT FROM AUTHOR]

3,4,5‐Trihydroxypiperidines belong to the family of 1,5‐dideoxy‐1,5‐iminosugar natural products and are structural analogues of pentose monosaccharides in the pyranose form. The biological activities of these apparently structurally simple molecules and their N‐ and O‐alkylated and ‐arylated derivatives are no less remarkable than their C‐6 hydroxymethyl counterparts of the hexoses (such as 1‐deoxynojirimycin, DNJ). Their biological profiles indicate that the hydroxymethyl branch is crucial to neither potency nor selectivity, with O‐alkylation demonstrated to produce exquisite selectivity extending beyond glycosidase inhibition, to immunosuppressant and antibacterial activities. [ABSTRACT FROM AUTHOR]

The effect of different leaving groups on the substitution versus elimination outcomes with C-5 D-glucose derivatives was investigated. The stereochemical configurations of 3-O-benzyl-1,2-O-isopropylidene-5-O-methanesulfonyl-6-Otriphenylmethyl-α-D-glucofuranose, C36H38O8S (3) [systematic name: 1-[(3aR,5R,6S,6aR)-6-benzyloxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol- 5-yl)-2-(trityloxy)ethyl methanesulfonate], a stable intermediate, and 5-azido-3- O-benzyl-5-deoxy-1,2-O-isopropylidene-6-O-triphenylmethyl-β-L-idofuranose, C35H35N3O5 (4) [systematic name: (3aR,5S,6S,6aR)-5-[1-azido-2-(trityloxy)ethyl]- 6-benzyloxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole], a substitution product, were examined and the inversion of configuration for the azido group on C-5 in 4 was confirmed. The absolute structures of the molecules in the crystals of both compounds were confirmed by resonant scattering. In the crystal of 3, neighbouring molecules are linked by C-H···O hydrogen bonds, forming chains along the b-axis direction. The chains are linked by C-H···π interactions, forming layers parallel to the ab plane. In the crystal of 4, molecules are also linked by C-H···O hydrogen bonds, forming this time helices along the a-axis direction. The helices are linked by a number of C-H···#960; interactions, forming a supramolecular framework. [ABSTRACT FROM AUTHOR]

The iminosugar 2,5-dideoxy-2,5-imino- d -altritol (DIA, 2 ) is a powerful competitive inhibitor of α-galactosidase A and has shown much promise as a pharmacological chaperone for the treatment for Fabry disease. Notwithstanding, syntheses of DIA are in want of optimisation. Accordingly, we report on the total synthesis of DIA in 7 steps and in 22% overall yield from readily available d -tagatose. This is the shortest and most efficient synthesis of DIA to date, with key steps in our synthetic strategy including a diastereoselective reductive amination and an I 2 -mediated carbamate annulation. [ABSTRACT FROM AUTHOR]

A short enantioselective total synthesis of 1-deoxygalactonojirimycin (migalastat) has been achieved that does not rely on chiral pool starting materials or biocatalysis. Instead, this synthesis exploits a one-pot proline-catalyzed α-chlorination and aldol reaction of a commercially available aldehyde to assemble the entire carbon skeleton in a single step. The key role played by a nitrogen protecting group in the final epoxide opening reaction is highlighted as is the amenability to access structural analogues using this route. [ABSTRACT FROM AUTHOR]

A series of 3 S ,4 S ,5 S -trihydroxylated piperidines bearing structural diversity at C-2 or C-6 positions has been synthesized and tested to determine their ability to stabilize the activity of recombinant human α-Galactosidase A (rh-α-Gal A). Hit molecules were identified by rapid inhibitory activity screening, and then further investigated for their ability to protect this enzyme from thermo-induced denaturation and enhance its activity in Fabry patient cell lines. Our study resulted in the identification of a new class of small molecules as enzyme stabilizers for the potential treatment of Fabry disease. Of these, stabilizer 21 was the most effective, showing a 12-fold increase in rh-α-Gal A activity in Fabry disease cell lines. [ABSTRACT FROM AUTHOR]

1-Deoxynojirimycin (1-DNJ) is a glycoprocessing inhibitor, and it serves as a synthetic precursor to two of three currently marketed iminosugar drugs, miglustat (N-butyl DNJ/Zavesca®) and miglitol (Glyset®). Herein a continuous flow procedure is presented that shortens a synthesis of 1-DNJ from an intermediate prepared from l -sorbose. Batch reactions involving an azide reduction, subsequent reductive amination-based cyclisation, and O -benzyl deprotection in a previous report required two steps and the use of an acid. Here, this sequence is achieved in one step using the H-Cube® MiniPlus continuous flow reactor. Subsequent reductive amination of 1-DNJ with butanal using the H-Cube® gave NB-DNJ. [Display omitted] • Continuous flow synthesis of 1-DNJ from an l -sorbose derivative. • Improved yield, reaction time and safety. • First flow synthesis of miglustat (Zavesca®). [ABSTRACT FROM AUTHOR]

Cancer cells of diverse origins express extracellular tumor-specific carbohydrate antigens (TACAs) because of aberrant glycosylation. Overexpressed TACAs on the surface of tumor cells are considered biomarkers for cancer detection and have always been prioritized for the development of novel carbohydrate-based anti-cancer vaccines. In recent years, progress has been made in developing synthetic, carbohydrate-based antitumor vaccines to improve immune responses associated with targeting these specific antigens. Tumor cells also exhaust more energy for proliferation than normal cells, by consuming excessive amounts of glucose via overexpressed sugar binding or transporting receptors located in the cellular membrane. Furthermore, inspired by the Warburg effect, glycoconjugation strategies of anticancer drugs have gained considerable attention from the scientific community. This review highlights a small cohort of recent efforts which have been made in carbohydrate-based cancer treatments, including vaccine design and the development of glycoconjugate prodrugs, glycosidase inhibiting iminosugars, and early cancer diagnosis.

Lucerastat, an inhibitor of glucosylceramide synthase, has the potential for substrate reduction therapy in glycosphingolipid storage disorders such as Fabry disease. In pharmacokinetic studies in rats, dogs, and healthy subjects, the main route of elimination was renal. The pharmacokinetics, tolerability, and safety of lucerastat were evaluated in subjects with mild (group A), moderate (group B), and severe (group C) renal impairment. Group D included healthy subjects. Thirty-two subjects (8 per group) were included in this single-center, open-label study and received a single oral dose of 1000 mg lucerastat in groups A and B and 500 mg in groups C and D. The degree of renal impairment of the subjects was based on estimated glomerular filtration rate. Plasma lucerastat concentrations (dose-corrected) were higher in groups B and C compared to group D. The elimination phase half-life was slower in groups B (9.6 hours) and C (16.1 hours) compared to group D (7.0 hours). Increased exposure to lucerastat was observed in subjects from groups B and C with ratio of geometric means (90%CI) of 1.60 (1.29, 1.98) for group B vs D and 3.17 (2.76, 3.65) for group C vs D. There were no clinically relevant abnormalities in vital signs, 12-lead electrocardiograms, and clinical laboratory values. Four nonserious adverse events were reported by 4 subjects (1 in group A, 3 in group D). Lucerastat was well tolerated in all dose groups. Dose adjustment is warranted in subjects with moderate and severe renal impairment. [ABSTRACT FROM AUTHOR]

Azanucleosides, sugar-modified nucleoside analogues containing a 4′ nitrogen atom, have shown a lot of therapeutic potential, e.g. as anti-cancer and antiviral agents. We report the synthesis of a series of 2’-homoazanucleosides, in which the nucleobase is attached to the 2’-position of the pyrrolidine ring via a methylene linker. A suitable orthogonally protected iminosugar was synthesized by ring closing metathesis and dihydroxylation as key steps and further converted to a series of 8 nucleoside analogues through Mitsunobu reaction with suitably protected nucleobases. The 5′ position of the adenine analogue was then further derivatized with thiols to afford 2 additional compounds. The final compounds were evaluated for biological activity. [ABSTRACT FROM AUTHOR]

Three new iminosugar-containing KRN7000 (also referred to as α- GalCer) analogues were designed and synthesized. In the design, the galactose moiety of KRN7000 was replaced by iminosugars and the iminosugar structures were connected with ceramide in different manners with a C-glycosidic bond instead of the O-glycosidic bond. To our knowledge, this is the first report in which iminosugars are incorporated in KRN7000 structure modifications. The synthetic compounds were evaluated for their ability to stimulate cytokine release. The results may benefit better understanding of structure-activity relationships and facilitate future design of more KRN7000 derivatives. [ABSTRACT FROM AUTHOR]

Intramolecular Huisgen azide-alkene cycloaddition reaction of 7-azido-hepta-1,5-diene-3,4-diols, prepared from methyl a-D-mannopyranoside, were carried out. Allylic azide rearrangement to secondary azides occurred in tandem with triazoline formation and this intermediate was then decomposed in the presence of nucleophilic reagents to give pyrrolidines, piperidines, or azepanes depending on whether cyclic constraint was incorporated or not, on diol stereochemistry and on the nucleophile. The tandem reaction worked best when aziridine formation from the triazoline was efficient, and this efficiency improved on removal of cyclic constraint. Proposals to account for the observed diastereoselectivities are provided. The allylic azide rearrangement in tandem with the intramolecular Huisgen azide-alkyne cycloaddition was also investigated from azidoheptaenyne diols and gave dihydropyrrolotriazoles. All reactions were diastereoselective, and this was high in some cases. Two X-ray crystal structural determinations, 13C NMR data, and 1D and 2D NOESY experiments were used for stereochemical assignments. [ABSTRACT FROM AUTHOR]

The enigmatical dichotomy between the two CERT/GPBP protein isoforms, their vast panel of biological implications and the scarcity of known antagonist series call for new ligand chemotypes identification. We report the design of iminosugar-based ceramide mimics for the development of new START domain ligands potentially targeting either protein isoforms. Strategic choice of (i) an iminoxylitol core structure and (ii) the positioning of two dodecyl residues led to an extent of protein binding comparable to that of the natural cargo lipid ceramide or the archetypical inhibitor HPA-12. Molecular docking study evidenced a possible mode of protein binding fully coherent with the one observed in crystalline co-structures of known ligands. The present study thus paves the way for cellular CERT inhibition studies en route to the development of pharmacological tools aiming at deciphering the respective function and therapeutic potential of the two CERT/GPBP protein isoforms. [ABSTRACT FROM AUTHOR]

Iminosugars are host-directed antivirals with broad-spectrum activity. The iminosugar, N -butyl-deoxynojirimycin ( N B-DNJ or Miglustat ® ), is used in humans for treatment of Gaucher's disease and has mild antiviral properties. More potent analogs of N B-DNJ have been generated and have demonstrated activity against a variety of viruses including flaviviruses, influenza, herpesviruses and filoviruses. In the current study, a panel of analogs based on N B-DNJ was analyzed for activity against Ebola (EBOV) and Marburg viruses (MARV). The antiviral activity of N B-DNJ (UV-1), UV-2, UV-3, UV-4 and UV-5 against both EBOV and MARV was demonstrated in Vero cells. Subsequent studies to examine the activity of UV-4 and UV-5 using rodent models of EBOV and MARV were performed. In vivo efficacy studies provided inconsistent data following treatment with iminosugars using filovirus mouse models. A tolerability study in nonhuman primates demonstrated that UV-4 could be administered at much higher dose levels than rodents. Since UV-4 was active in vitro , had been demonstrated to be active against influenza and dengue in vivo , and was being tested in a Phase 1 clinical trial, a small proof-of-concept nonhuman primate trial was performed to determine whether this antiviral candidate could provide clinical benefit to EBOV-infected individuals. Administration of UV-4B did not provide a clinical or survival benefit to macaques infected with EBOV–Makona; however, dosing of animals was not optimal in this study. Efficacy may be improved by thrice daily dosing (e.g. by nasogastric tube feeding) to match the efficacious dosing regimens demonstrated against dengue and influenza viruses. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease. The disease involves excessive accumulation of fibroblasts and myofibroblasts, and myofibroblasts differentiated by pro-fibrotic factors promote the deposition of extracellular matrix proteins such as collagen and fibronectin. Transforming growth factor-β1 is a pro-fibrotic factor that promotes fibroblast-to-myofibroblast differentiation (FMD). Therefore, inhibition of FMD may be an effective strategy for IPF treatment. In this study, we screened the anti-FMD effects of various iminosugars and showed that some compounds, including N-butyldeoxynojirimycin (NB-DNJ, miglustat, an inhibitor of glucosylceramide synthase (GCS)), a clinically approved drug for treating Niemann–Pick disease type C and Gaucher disease type 1, inhibited TGF-β1-induced FMD by inhibiting the nuclear translocation of Smad2/3. N-butyldeoxygalactonojirimycin having GCS inhibitory effect did not attenuate the TGF-β1-induced FMD, suggesting that NB-DNJ exerts the anti-FMD effects by GCS inhibitory effect independent manner. N-butyldeoxynojirimycin did not inhibit TGF-β1-induced Smad2/3 phosphorylation. In a mouse model of bleomycin (BLM)-induced pulmonary fibrosis, intratracheal or oral administration of NB-DNJ at an early fibrotic stage markedly ameliorated lung injury and deterioration of respiratory functions, such as specific airway resistance, tidal volume, and peak expiratory flow. Furthermore, the anti-fibrotic effects of NB-DNJ in the BLM-induced lung injury model were similar to those of pirfenidone and nintedanib, which are clinically approved drugs for the treatment of IPF. These results suggest that NB-DNJ may be effective for IPF treatment. [ABSTRACT FROM AUTHOR]

A new synthetic approach to (+)-batzellaside B from naturally abundant L-pyroglutamic acid is presented in this article. The key synthetic step involves Sharpless asymmetric dihydroxylation of an olefinic substrate functionalized with an acetoxy group to introduce two chiral centres diastereoselectively into the structure. Heterocyclic hemiaminal 4, which could be converted from the resulting product, was found to provide stereospecific access to enantiomerically enriched allylated intermediate, offering better prospects for the total synthesis of this natural product.

[Display omitted] • The strong binding interactions of multivalent glycosidase inhibitors with enzymes were related to the efficient inhibitory activity against glycosidase. • The lengths of the chain between DNJ moieties and the triazole ring for the naphthalimide-DNJ conjugates influenced the self-assembly properties, binding interactions and glycosidase inhibition activities. • Detection of multivalent glycosidase inhibition effect by a fluorescent sensing method was developed. • Multivalency was a strategy to improve glycosidase inhibition activity. Synthetic glycoconjugates as chemical probes have been widely developed for the detection of glycosidase enzymes. However, the binding interactions between iminosugar derivatives and glycosidases were limited, especially for the binding interactions between multivalent glycosidase inhibitors and α-glycosidases. In this paper, three naphthalimide-DNJ conjugates were synthesized. Furthermore, the binding interactions and glycosidase inhibition effects of them were investigated. It was found that the strong binding interactions of multivalent glycosidase inhibitors with enzymes were related to the efficient inhibitory activity against glycosidase. Moreover, the lengths of the chain between DNJ moieties and the triazole ring for the naphthalimide-DNJ conjugates influenced the self-assembly properties, binding interactions and glycosidase inhibition activities with multisource glycosidases. Compound 13 with six carbons between the DNJ moiety and triazole ring showed the stronger binding interactions and better glycosidase inhibition activities against α-mannosidase (jack bean) and α-glucosidase (aspergillus niger). In addition, compound 13 showed an effective PBG inhibition effect in mice with 51.18 % decrease in blood glucose at 30 min. This result opens a way for detection of multivalent glycosidase inhibition effect by a fluorescent sensing method. [ABSTRACT FROM AUTHOR]

[Display omitted] • A 16-membered ADMDP library including all diastereomers was evaluated. • The best configuration pattern of pyrrolidines was identified to stabilize GAA. • The derivatives were synthesized through internal and external modifications. • The most potent stabilizer 21 was found to prevent rh-GAA from denaturation. • Stabilizer 21 showed a 5.1-fold increase in rh-GAA activity in Pompe fibroblasts. To discover small molecules as acid alpha-glucosidase (GAA) stabilizers for potential benefits of the exogenous enzyme treatment toward Pompe disease cells, we started from the initial screening of the unique chemical space, consisting of sixteen stereoisomers of 2-aminomethyl polyhydroxylated pyrrolidines (ADMDPs) to find out two primary stabilizers 17 and 18. Further external or internal structural modifications of 17 and 18 were performed to increase structural diversity, followed by the protein thermal shift study to evaluate the GAA stabilizing ability. Fortunately, pyrrolidine 21 , possessing an l - arabino -typed configuration pattern, was identified as a specific potent rh-GAA stabilizer, enabling the suppression of rh-GAA protein denaturation. In a cell-based Pompe model, co-administration of 21 with rh-GAA protein significantly improved enzymatic activity (up to 5-fold) compared to administration of enzyme alone. Potentially, pyrrolidine 21 enables the direct increase of ERT (enzyme replacement therapy) efficacy in cellulo and in vivo. [ABSTRACT FROM AUTHOR]

Background: According to the World Health Organization, osteoarthritis (OA) is one of the 10 most disabling diseases in developed countries, with worldwide estimates of 9.6% prevalence in men and 18.0% in women over 60 years old. Its management is not well established and involves the use of high doses of painkillers coupled with anti-inflammatory agents., Objective: In the search for alternatives to manage the disease, previous studies have shown superior properties of Q-Actin TM in managing OA-related pain compared with standard treatments. Qactin is a cucumber extract with the anti-inflammatory iminosugar idoBR1 standardised to over 1%. This study investigated the effects of different doses (20 mg, 100 mg) of Q-Actin in a longitudinal placebo-controlled experiment., Methods: There were 101 patients with knee OA enrolled for the 180-day study, with 91 patients completing it. Patients were grouped into a placebo group (PLBO), as well as a 20mg dose (Q-Actin 1) and 100 mg dose (Q-Actin 2) groups. The PLBO group received cellulose in capsules identical to the Q-Actin capsules., Results: There was a significant improvement in the pain-related parameters over time that was dose-dependent., Conclusion: This study clearly demonstrated the effectiveness of Q-Actin compared to placebo in the management of pain related to moderate osteoarthritis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Peracetylated N-α-azidoacetylmannosamine (Ac4ManNAz) is metabolized by cells to CMP-azidosialic acid. It has been demonstrated previously that in this way azidosialic acid-containing glycoproteins are formed that can be labeled on the cell surface by a modified Staudinger ligation. Here, we first demonstrate that the same procedure also results in the formation of azidosialic acid-containing gangliosides. Deoxymannojirimycin, an inhibitor of N-glycan processing in proteins, decreases the total cell surface labeling in Jurkat cells by ∼25%. Inhibition of ganglioside biosynthesis with N-[5-(adamantan-1-yl-methoxy)-pentyl]1-deoxynojirimycin reduces cell surface labeling by ∼75%. In conclusion, exposure of cells to Ac4ManNAz allows in vivo chemical tagging of gangliosides.