155501-85-2

Upstream product

• 109-65-9 1-bromo-butane 
• 19130-96-2 1,5-dideoxy-1,5-imino-D-glucitol 
• 6564-72-3 2,3,4,6-tetra-O-benzyl-D-glucopyranose 
• 1316108-84-5 (2S,3R,4R,5R)-2,3,4,6-tetrakis(benzyloxy)-5-hydroxyhexyl pivalate 
• 1316108-89-0 (2R,3R,4R,5S)-1,3,4,5-tetrakis(benzyloxy)-6-(pivaloyloxy)hexan-2-yl benzoate 
• 4291-69-4 2,3,4,6-Tetra-O-benzyl-D-glucopyranose 
• 78136-16-0 (2S,3R,4R,5S)-2,3,4,6-tetrakis(benzyloxy)hexane-1,5-diol 
• 139189-61-0 2,3,4,6-tetra-O-benzyl-D-xylo-hex-5-ulosononitrile 
• 97-30-3 methyl-alpha-D-glucopyranoside 
• 76670-94-5 2,3,4,6-tetra-O-benzyl-5-dehydro-5-oxo-D-gluconamide 
• 3879-79-6 methyl 2,3,4,6-tetra-O-benzyl-α-D-glucopyranoside 
• 13096-62-3 (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-one 
• 76670-93-4 2,3,4,6-tetra-O-benzyl-D-gluconamide 
• 77174-08-4 (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)piperidin-2-one 

Relevant academic research and scientific papers

Bioconversion of N-butylglucamine to 6-deoxy-6-butylamino sorbose by Gluconobacter oxydans

Gluconobacter oxydans has the unique ability to regioselectively and rapidly oxidize sorbitol and other erythro saccharides. In this report a new process is described by which N-butylglucamine is regioselectively oxidized by the organism. A largescale process is described by which N-butylglucamine can be converted to an intermediate (6-deoxy-6-butylaminosorbose) which can be readily converted to N-butyldeoxynojirimycin by catalytic hydrogenation. The primary process variables of temperature, pH, and added acids and salts were investigated in laboratory bioreactors. Since degradation of the sorbose product was rapid above room temperature, significant enhancement of the selectivity was achieved by lowering the temperature at which the bioconversion was run. The optimum temperature for this conversion was 12-15°C. The pH maximum of the bioconversion was 5.5-6.0. However, the small gain in rate relative to pH 5.0 was at least offset by the increase in degradation of the product at the higher pH. Nitrate salts of N-butylglucamine could replace chloride salts, but sulfate, acetate, and phosphate salts could not. Sulfate in particular led to inhibition of the conversion, while phosphate and acetate led to increased degradation. At temperatures in the range of 12-15°C, pH of around 5.0 and substrate concentrations of 0.2 M, Gluconobacter oxydans catalyzed bioconversion to 6-deoxy-6-butylaminosorbose with yields approaching 95%. These conditions were used to scale this process to 5500-L scale.

α-1-C-Octyl-1-deoxynojirimycin as a pharmacological chaperone for Gaucher disease

The most common lysosomal storage disorder, Gaucher disease, is caused by inefficient folding and trafficking of certain variants of lysosomal β-glucosidase (β-Glu, also known as β-glucocerebrosidase). Recently, Sawker et al. reported that the addition of subinhibitory concentrations (10 μM) of the pharmacological chaperone N-nonyl-1-deoxynojirimycin (NN-DNJ) (10) to Gaucher patient-derived cells leads to a 2-fold increase in activity of mutant (N370S) enzyme [Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 15428]. However, we found that the addition of NN-DNJ at 10 μM lowered the lysosomal α-glucosidase (α-Glu) activity by 50% throughout the assay period in spite of the excellent chaperoning activity in N370S fibroblasts. Hence, we prepared a series of DNJ derivatives with an alkyl chain at the C-1α position and evaluated their in vitro inhibitory activity and potential as pharmacological chaperones for Gaucher cell lines. Among them, α-1-C-octyl-DNJ (CO-DNJ) (15) showed 460-fold stronger in vitro inhibitory activity than DNJ toward β-Glu, while NN-DNJ enhanced in vitro inhibitory activity by 360-fold. Treatment with CO-DNJ (20 μM) for 4 days maximally increased intracellular β-Glu activity by 1.7-fold in Gaucher N370 cell line (GM0037) and by 2.0-fold in another N370 cell line (GM00852). The addition of 20 μM CO-DNJ to the N370S (GM00372) culture medium for 10 days led to 1.9-fold increase in the β-Glu activity without affecting the intracellular α-Glu activity for 10 days. Only CO-DNJ showed a weak β-Glu chaperoning activity in the L444P type 2 variant, with 1.2-fold increase at 5-20 μM, and furthermore maximally increased the α-Glu activity by 1.3-fold at 20 μM. These experimental results suggest that CO-DNJ is a significant pharmacological chaperone for N370S Gaucher variants, minimizing the potential for undesirable side effects such as α-Glu inhibition.

N-Butyl-l-deoxynojirimycin (l-NBDNJ): Synthesis of an Allosteric Enhancer of α-Glucosidase Activity for the Treatment of Pompe Disease

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.

Iminosugars: Effects of stereochemistry, ring size, and n-substituents on glucosidase activities

N-substituted iminosugar analogues are potent inhibitors of glucosidases and glycosyltransferases with broad therapeutic applications, such as treatment of diabetes and Gaucher disease, immunosuppressive activities, and antibacterial and antiviral effects against HIV, HPV, hepatitis C, bovine diarrhea (BVDV), Ebola (EBOV) and Marburg viruses (MARV), influenza, Zika, and dengue virus. Based on our previous work on functionalized isomeric 1,5-dideoxy-1,5-imino-D-gulitol (L-gulo-piperidines, with inverted configuration at C-2 and C-5 in respect to glucose or deoxynojirimycin (DNJ)) and 1,6-dideoxy-1,6-imino-D-mannitol (D-manno-azepane derivatives) cores N-linked to different sites of glucopyranose units, we continue our studies on these alternative iminosugars bearing simple N-alkyl chains instead of glucose to understand if these easily accessed scaffolds could preserve the inhibition profile of the corresponding glucose-based N-alkyl derivatives as DNJ cores found in miglustat and miglitol drugs. Thus, a small library of iminosugars (14 compounds) displaying different stereochemistry, ring size, and N-substitutions was successfully synthesized from a common precursor, D-mannitol, by utilizing an SN2 aminocyclization reaction via two isomeric bis-epoxides. The evaluation of the prospective inhibitors on glucosidases revealed that merely D-gluco-piperidine (miglitol, 41a) and L-ido-azepane (41b) DNJ-derivatives bearing the N-hydroxylethyl group showed inhibition towards α-glucosidase with IC50 41 μM and 138 μM, respectively, using DNJ as reference (IC50 134 μM). On the other hand, β-glucosidase inhibition was achieved for glucose-inverted configuration (C-2 and C-5) derivatives, as novel L-gulo-piperidine (27a) and D-manno-azepane (27b), preserving the N-butyl chain, with IC50 109 and 184 μM, respectively, comparable to miglustat with the same N-butyl substituent (40a, IC50 172 μM). Interestingly, the seven-membered ring L-ido-azepane (40b) displayed near twice the activity (IC50 80 μM) of the corresponding D-gluco-piperidine miglustat drug (40a). Furthermore, besides α-glucosidase inhibition, both miglitol (41a) and L-ido-azepane (41b) proved to be the strongest β-glucosidase inhibitors of the series with IC50 of 4 μM.

A Fluorescence Polarization Activity-Based Protein Profiling Assay in the Discovery of Potent, Selective Inhibitors for Human Nonlysosomal Glucosylceramidase

Human nonlysosomal glucosylceramidase (GBA2) is one of several enzymes that controls levels of glycolipids and whose activity is linked to several human disease states. There is a major need to design or discover selective GBA2 inhibitors both as chemical tools and as potential therapeutic agents. Here, we describe the development of a fluorescence polarization activity-based protein profiling (FluoPol-ABPP) assay for the rapid identification, from a 350+ library of iminosugars, of GBA2 inhibitors. A focused library is generated based on leads from the FluoPol-ABPP screen and assessed on GBA2 selectivity offset against the other glucosylceramide metabolizing enzymes, glucosylceramide synthase (GCS), lysosomal glucosylceramidase (GBA), and the cytosolic retaining β-glucosidase, GBA3. Our work, yielding potent and selective GBA2 inhibitors, also provides a roadmap for the development of high-throughput assays for identifying retaining glycosidase inhibitors by FluoPol-ABPP on cell extracts containing recombinant, overexpressed glycosidase as the easily accessible enzyme source.

Structure–Activity Studies of N-Butyl-1-deoxynojirimycin (NB-DNJ) Analogues: Discovery of Potent and Selective Aminocyclopentitol Inhibitors of GBA1 and GBA2

Analogues of N-butyl-1-deoxynojirimycin (NB-DNJ) were prepared and assayed for inhibition of ceramide-specific glucosyltransferase (CGT), non-lysosomal β-glucosidase 2 (GBA2) and the lysosomal β-glucosidase 1 (GBA1). Compounds 5 a–6 f, which carry sterically demanding nitrogen substituents, and compound 13, devoid of the C3 and C5 hydroxy groups present in DNJ/NB-DGJ (N-butyldeoxygalactojirimycin) showed no inhibitory activity for CGT or GBA2. Inversion of stereochemistry at C4 of N-(n-butyl)- and N-(n-nonyl)-DGJ (compounds 24) also led to a loss of activity in these assays. The aminocyclopentitols N-(n-butyl)- (35 a), N-(n-nonyl)-4-amino-5-(hydroxymethyl)cyclopentane- (35 b), and N-(1-(pentyloxy)methyl)adamantan-1-yl)-1,2,3-triol (35 f), were found to be selective inhibitors of GBA1 and GBA2 that did not inhibit CGT (>1 mm), with the exception of 35 f, which inhibited CGT with an IC50 value of 1 mm. The N-butyl analogue 35 a was 100-fold selective for inhibiting GBA1 over GBA2 (Ki values of 32 nm and 3.3 μm for GBA1 and GBA2, respectively). The N-nonyl analogue 35 b displayed a Ki value of ?14 nm for GBA1 inhibition and a Ki of 43 nm for GBA2. The N-(1-(pentyloxy)methyl)adamantan-1-yl) derivative 35 f had Ki values of ≈16 and 14 nm for GBA1 and GBA2, respectively. The related N-bis-substituted aminocyclopentitols were found to be significantly less potent inhibitors than their mono-substituted analogues. The aminocyclopentitol scaffold should hold promise for further inhibitor development.

Total synthesis of N-butyl-1-deoxynojirimycin

N-Butyl-1-deoxynojirimycin (NB-DNJ) derived from imino sugar deoxynojirimycin (DNJ) has been approved for the treatment of Gaucher’s disease. Herein, a facile and efficient synthetic procedure for NB-DNJ has been described. Comparing to the methods reported previously,methanesulfonyl group was used as a leaving group for easy displacement upon attack by the imine in the sugar ring, leading to a high yield during the introduction of the n-butyl group. Thismethod can serve as an excellent protocol for the synthesis of DNJ derivatives with a variety of N-alkyl substituents and for large-scale production.

One pot oxidative dehydration - oxidation of polyhydroxyhexanal oxime to polyhydroxy oxohexanenitrile: A versatile methodology for the facile access of azasugar alkaloids

A unique oxidative dehydration-oxidation of polyhydroxy-oxime (7) to the corresponding ketonitrile (8) in one pot is reported for the first time in carbohydrate literature. Key ketonitrile intermediate (8) upon palladium hydroxide mediated cascade reaction afforded 1-deoxynojirimycin (DNJ) 1b in moderate diastereoselectivity. The cascade reaction involves the conversion of nitrile to amine, heteroannulation, reduction of the imine and subsequent debenzylation to furnish the azasugars. This oxidative dehydration-oxidation and reductive heteroannulation methodology is successfully utilized for the total synthesis of 1-deoxynojirimycin (1b), miglitol (2) and miglustat (3).

Three-step synthesis of l-: Ido -1-deoxynojirimycin derivatives by reductive amination in water, borrowing hydrogen under neat conditions and deprotection

In this communication, we describe a three-step synthesis of l-ido-1-deoxynojirimycin derivatives starting from readily available 2,3,4,6-tetra-O-benzyl-d-glucopyranose via Ir-catalyzed reductive amination in water, borrowing hydrogen under neat conditions, and Pd-catalyzed debenzylation.

Process For The Preparation Of High Purity Miglustat

A process for the preparation and isolation of crystalline miglustat without the use of a column chromatography or ion exchange purification. The crystalline miglustat has a high purity and a melting point of 128° C. and an endothermic peak is 133° C.