- Iminosugars: Effects of stereochemistry, ring size, and n-substituents on glucosidase activities
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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.
- Zamoner, Luís O. B.,Arag?o-Leoneti, Valquiria,Carvalho, Ivone
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- A Fluorescence Polarization Activity-Based Protein Profiling Assay in the Discovery of Potent, Selective Inhibitors for Human Nonlysosomal Glucosylceramidase
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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.
- Lahav, Dani?l,Liu, Bing,Van Den Berg, Richard J.B.H.N.,Van Den Nieuwendijk, Adrianus M. C. H.,Wennekes, Tom,Ghisaidoobe, Amar T.,Breen, Imogen,Ferraz, Maria J.,Kuo, Chi-Lin,Wu, Liang,Geurink, Paul P.,Ovaa, Huib,Van Der Marel, Gijsbert A.,Van Der Stelt, Mario,Boot, Rolf G.,Davies, Gideon J.,Aerts, Johannes M. F. G.,Overkleeft, Herman S.
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p. 14192 - 14197
(2017/10/17)
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- Total synthesis of N-butyl-1-deoxynojirimycin
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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.
- Wang, Jiajia,Zhao, Yunyan,Zhao, Wei,Wang, Peng,Li, Jing
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p. 445 - 454
(2017/08/23)
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- One pot oxidative dehydration - oxidation of polyhydroxyhexanal oxime to polyhydroxy oxohexanenitrile: A versatile methodology for the facile access of azasugar alkaloids
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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).
- Khobare, Sandip R.,Gajare, Vikas,Reddy, E. Vishnuvardhan,Datrika, Rajender,Banda, Malavika,Siddaiah, Vidavalur,Pachore, Sharad S.,Timanna, Upadhya,Dahanukar, Vilas H.,Syam Kumar
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- Process For The Preparation Of High Purity Miglustat
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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.
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- IMINOSUGAR IN CRYSTALLINE FORM
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Iminosugar, which possesses known activity as a glycosyltransferase inhibitor, and is used, for example, in the treatment of Gaucher's disease, in crystalline form, a process for its preparation and a pharmaceutical composition thereof.
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Paragraph 0072
(2014/08/06)
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- SYNTHESIS OF A GLYCOSYLTRANSFERASE INHIBITOR
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Process for the preparation of animinosugar, and the intermediates thereof, having known activity as a glycosyltransferase inhibitor and used, for example, in the treatment of Gaucher's disease.
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Paragraph 0057
(2014/09/03)
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- α-1-C-Butyl-1,4-Dideoxy-1,4-Imino-L-Arabinitol as a second-Generation iminosugar-based oral α-Glucosidase inhibitor for improving postprandial hyperglycemia
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We report on the synthesis and the biological evaluation of a series of α-1-C-alkylated 1,4-dideoxy-1,4-imino-l-arabinitol (LAB) derivatives. The asymmetric synthesis of the derivatives was achieved by asymmetric allylic alkylation, ring-closing metathesis, and Negishi cross-coupling as key reactions. α-1-C-Butyl-LAB is a potent inhibitor of intestinal maltase, isomaltase, and sucrase, with IC50 values of 0.13, 4.7, and 0.032 μM, respectively. Matrix-assisted laser desorption ionization time-of-flight mass spectrometric analysis revealed that this compound differs from miglitol in that it does not influence oligosaccharide processing and the maturation of glycoproteins. A molecular docking study of maltase-glucoamylase suggested that the interaction modes and the orientations of α-1-C-butyl-LAB and miglitol are clearly different. Furthermore, α-1-C-butyl-LAB strongly suppressed postprandial hyperglycemia at an early phase, similar to miglitol in vivo. It is noteworthy that the effective dose was about 10-fold lower than that for miglitol. α-1-C-Butyl-LAB therefore represents a new class of promising compounds that can improve postprandial hyperglycemia.
- Kato, Atsushi,Hayashi, Erina,Miyauchi, Saori,Adachi, Isao,Imahori, Tatsushi,Natori, Yoshihiro,Yoshimura, Yuichi,Nash, Robert J.,Shimaoka, Hideyuki,Nakagome, Izumi,Koseki, Jun,Hirono, Shuichi,Takahata, Hiroki
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p. 10347 - 10362
(2013/02/23)
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- Facile and stereo-controlled synthesis of 2-deoxynojirimycin, Miglustat and Miglitol
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A novel and facile synthesis of a series of the biologically significant iminosugar derivatives including 2-deoxynojirimycin, Miglustat and Miglitol is reported. The synthesis features a strategic double inversion mechanism for securing the desired stereochemistry at C5 position of such glucose-type carbohydrate mimetics, representing a practical and remarkable improvement on the previously reported method that suffers from the loss of the stereo-control during the reaction process. Crown Copyright
- Zhang, Zhen-Xing,Wu, Baolin,Wang, Bin,Li, Tie-Hai,Zhang, Peng-Fei,Guo, Li-Na,Wang, Wen-Jun,Zhao, Wei,Wang, Peng George
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p. 3802 - 3804
(2011/08/09)
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- Identification of potent and selective glucosylceramide synthase inhibitors from a library of N-alkylated iminosugars
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Glucosylceramide synthase (GCS) is an important target for clinical drug development for the treatment of lysosomal storage disorders and a promising target for combating type 2 diabetes. Iminosugars are useful leads for the development of GCS inhibitors; however, the effective iminosugar type GCS inhibitors reported have some unwanted cross-reactivity toward other glyco-processing enzymes. In particular, iminosugar type GCS inhibitors often also inhibit to some extent human acid glucosylceramidase (GBA1) and the nonlysosomal glucosylceramidase (GBA2), the two enzymes known to process glucosylceramide. Of these, GBA1 itself is a potential drug target for the treatment of the lysosomal storage disorder, Gaucher disease, and selective GBA1 inhibitors are sought after as potential chemical chaperones. The physiological importance of GBA2 in glucosylceramide processing in relation to disease states is less clear, and here, selective inhibitors can be of use as chemical knockout entities. In this communication, we report our identification of a highly potent and selective N-alkylated l-ido-configured iminosugar. In particular, the selectivity of 27 for GCS over GBA1 is striking.
- Ghisaidoobe, Amar,Bikker, Pieter,De Bruijn, Arjan C. J.,Godschalk, Frithjof D.,Rogaar, Eva,Guijt, Marieke C.,Hagens, Peter,Halma, Jerre M.,Van't Hart, Steven M.,Luitjens, Stijn B.,Van Rixel, Vincent H. S.,Wijzenbroek, Mark,Zweegers, Thor,Donker-Koopman, Wilma E.,Strijland, Anneke,Boot, Rolf,Van Der Marel, Gijs,Overkleeft, Herman S.,Aerts, Johannes M. F. G.,Van Den Berg, Richard J. B. H. N.
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body text
p. 119 - 123
(2011/04/15)
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- D-fructose-6-phosphate aldolase in organic synthesis: Cascade chemical-enzymatic preparation of sugar-relafed polyhydroxylated compounds
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Novel aldol addition reactions of dihydroxyacetone (DHA) and hydroxyacetone (HA) to a variety of aldehydes catalyzed by D-fructose-6-phosphate aldolase (FSA) are presented. In a chemical-enzymatic cascade reaction approach, 1-deoxynojirimycin and 1-deoxymannojirimycin were synthesized starting from (R)- and (S)-3-(N-Cbz-amino)-2-hydroxypropanal, respectively. Furthermore, 1,4-dideoxy1,4-imino-D-arabinitol and 1,4,5-trideoxy-1,4-imino-D-arabinitol were prepared from N-Cbz-glycinal, 1 -Deoxy-D-xylulose was also synthesized by using HA as the donor and either 2-benzyloxyethanal or 2-hydroxyethanal as acceptors. In both cases the enzymatic aldol addition reaction was fully stereoselective, but with 2-hydroxyethanal 17% of the epimeric product at C2, 1-deoxy-D-erythro-2-pentulose, was observed due to enolization/epimerization during the isolation steps. It was also observed that D-(-)-threose is a good acceptor substrate for FSA, opening new synthetic possibilities for the preparation of important novel complex carbohydrate-related compounds from aldoses. To illustrate this, 1-deoxy-D-ido-hept-2-ulose was obtained stereoselectively by the addition of HA to D-(-)-threose, catalyzed by FSA. It was found that the reaction performance depended strongly on the donor substrate, HA being the one that gave the best conversions to the aldol adduct. The examples presented in this work show the valuable synthetic potential of FSA for the construction of chiral complex polyhydroxylated sugar-type structures.
- Concia, Alda Lisa,Lozano, Caries,Castillo, Jose A.,Parella, Teodor,Joglar, Jesus,Clapes, Pere
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experimental part
p. 3808 - 3816
(2010/01/16)
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- COMPOSITIONS COMPRISING NB-DNJ, NE-DNJ OR D-GLUCARO-DELTA-LACTAM AND THEIR USES FOR THE TREATMENT OF PAIN AND OTHER NEUROLOGICAL CONDITIONS
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Methods and compositions for the treatment of conditions including stress-associated, chronic pain, and neurodegenerative conditions in a mammal using a composition comprising NB-DNJ or a compound structurally similar thereto.
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Page/Page column 46-47
(2008/06/13)
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- α-1-C-Octyl-1-deoxynojirimycin as a pharmacological chaperone for Gaucher disease
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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.
- Yu, Liang,Ikeda, Kyoko,Kato, Atsushi,Adachi, Isao,Godin, Guillaume,Compain, Philippe,Martin, Olivier,Asano, Naoki
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p. 7736 - 7744
(2007/10/03)
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- Use of n-substituted-1,5-dideoxy-1,5-imino-d-glucitol compounds for treating hepatitis virus infections
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Provided are methods and compositions for treating hepatitis virus infections in mammals, especially humans. The methods comprise (1) administering N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds alone or in combination with nucleoside antiviral agents, nucleotide antiviral agents, mixtures thereof, or immunomodulating/immunostimulating agents, or (2) administering N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds alone or in combination with nucleoside antiviral agents, nucleotide antiviral agents, or mixtures thereof, and immunomodulating/immuno-stimulating agents.
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- Use of N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds for treating hepatitis virus infections
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Provided are methods and compositions for treating hepatitis virus infections in mammals, especially humans. The methods comprise (1) administering N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds alone or in combination with nucleoside antiviral agents, nucleotide antiviral agents, mixtures thereof, or immunomodulating/immunostimulating agents, or (2) administering N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds alone or in combination with nucleoside antiviral agents, nucleotide antiviral agents, or mixtures thereof, and immunomodulating/immuno-stimulating agents.
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- Use of N-substituted-1, 5-dideoxy-1, 5-imino-D-glucitol compounds for treating hepatitis virus infections
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Provided are methods and compositions for treating hepatitis virus infections in mammals, especially humans. The methods comprise (1) administering N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds alone or in combination with nucleoside antiviral agents, nucleotide antiviral agents, mixtures thereof, or immunomodulating/immunostimulating agents, or (2) administering N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds alone or in combination with nucleoside antiviral agents, nucleotide antiviral agents, or mixtures thereof, and immunomodulating/immuno-stimulating agents.
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- Glucamine compounds for treating hepatitis virus infections
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N-Substituted glucamine compounds of Formula I are effective in treatment of hepatitis infections, including hepatitis B and hepatitis C. In treating hepatitis infections, the compounds of Formula I may be used alone, or in combination with another antiviral agents selected from among nucleosides, nucleotides, immunomodulators, immunostimulants or various combinations of such other agents.
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- Use of substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds for treating hepatitis virus infections
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N-Substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds of Formula I are effective in treatment of hepatitis infections, including hepatitis B and hepatitis C. In treating hepatitis infections, the compounds of Formula I may be used alone, or in combination with another antiviral agent selected from among nucleosides, nucleotides, immunomodulators, immunostimulats or various combinations of such other agents.
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- USE OF N-SUBSTITUTED-1,5-DIDEOXY-1,5-IMINO-D-GLUCITOL COMPOUNDS IN COMBINATION THERAPY FOR TREATING HEPATITIS VIRUS INFECTIONS
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Provided are methods and compositions for treating hepatitis virus infections in mammals, especially humans. The methods comprise (1) administering N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds in combination with nucleoside antiviral agents, nucleotide antiviral agents, mixtures thereof, or immunomodulating/immunostimulating agents, or (2) administering N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds in combination with nucleoside antiviral agents, nucleotide antiviral agents, or mixtures thereof, and immunomodulating/immunostimulating agents.
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- Bioconversion of N-butylglucamine to 6-deoxy-6-butylamino sorbose by Gluconobacter oxydans
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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.
- Landis, Bryan H.,McLaughlin, Joseph K.,Heeren, Robert,Grabner, Roy W.,Wang, Ping T.
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p. 547 - 552
(2013/09/06)
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- Use of alkylated iminosugars to treat multidrug resistance
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Methods and compositions for preventing, reducing, or reversing multidrug resistance (MDR) during cancer chemotherapy in patients undergoing treatment with therapeutically effective amounts of chemotherapeutic agents are provided. The methods comprise administering an anti-MDR effective amount of an N-substituted-1,5-dideoxy-1,5-imino-D-glucitol or galactitol iminosugar to a patient.
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- Synthesis of 1-deoxynojirimycin and N-butyl-1-deoxynojirimycin
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1-Deoxynojirimycin (1) is a natural alkaloid with several biological activities; the analog N-butyl-1-deoxynojirimycin (4), for example has shown potent anti HIV-1 and HIV-2 activity without cytotoxicity. As part of a program to synthesize compounds with biological activity against retroviruses, we developed an efficient route for the preparation of 1 and 4 employing as raw material glucose and others inexpensive reagents.
- Matos, Carlos R. R.,Lopes, Rosangela S. C.,Lopes, Claudio C.
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p. 571 - 573
(2007/10/03)
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- Method for treating a mammal infected with respiratory syncytial virus
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A method is provided for treating a mammal infected with respiratory syncytial virus (RSV) comprising administering to the mammal an RSV inhibitory effective amount of a compound or its pharmaceutically acceptable salt of the formula STR1 wherein R1 is alkyl, aralkyl, aroyl or acyl and R2, R3, R4 and R5 are H or acyl.
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- 2-CHLORO AND 2-BROMO DERIVATIVES OF 1,5-IMINOSUGARS
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Novel 2-chloro and 2-bromo derivatives of 1,5-iminosugars are disclosed, especially such derivatives of l,5-dideoxy-l,5-imino-D-glucitol. These compounds are useful inhibitors of glucosidase enzymes and also are useful as antiviral agents and as intermediates for the synthesis of other enzyme inhibitors and antiviral compounds
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- N-Alkylated Nitrogen-in-the-Ring Sugars: Conformational Basis of Inhibitiopn of Glycosidases and HIV-1 Replication
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The conformations of nitrogen-in-the-ring sugars and their N-alkyl derivatives were studied from 1H NMR analyses, mainly using 3J(H,H) coupling constants and quantitative NOE experiments.No significant difference was seen in the ring conformation of 1-deoxynojirimycin (1), N-methyl-1-deoxynojirimycin (2), and N-butyl-1-deoxynojirimycin (3).Hiowever, it was shown that the C6 OH group in 1 is predominantly equatorial to the piperidine ring, while that in 2 or 3 is predominantly axial, and its N-alkyl group is oriented equatorially.In the furanose analogues 1,4-dideoxy-1,4-imino-D-arabinitol (4) and its N-methyl (5) and N-butyl (6) derivatives, the five-membered ring conformation differed significvantly by the presence or absence of the N-substituted group and the length of the N-alkyl chain.Compound 3 reduced its inhibitory effect on almost all glycosidases, resulting in an extremely specific inhibitor for processing α-glucosidase I since N-alkylation of 1 is known to enhance both the potency and specificity of this enzyme in vitro and in vivo.This preferred (C6 OH axial) conformation in 2 and 3 appears to be responsible for their strong α-glucosidase I activity.Compound 4 is a good inhibitor of intestinal α-glucohydrolases, α-glucosidase II, and Golgi α-mannosidases I and II, but is N-alkyl derivatives 5 and 6 markedly decreased inhibitory potential for all enzymes tested.In the case of 2,5-dideoy-2,5-imino-D-mannitol (DMDP, 7), which is a potent toward β-galactosidase inhibitor, its N-methyl (8) and N-butyl (9) derivatives completely lost potency β-galactosidase as well.N-alkylation of compounds 4 and 7, known well as potent yeast α-glucosidase inhibitors, resulted in a serious loss of inhi bitory activity toward yeast α-glucohydrolases.Activity of these nine sugar analogues against HIV-1 replication was determined, based on the inhibition of virus-induced cytopathogenicity in MT-4 and MOLT-4 cells.Compounds 2 and 3, which are better inhibitors of α-glucosidase I than 1, proved active with EC50 values of 69 and 49 μg/mL in MT-4 cells and 100 and 37 μg/mL in MOLT-4 cells, respectively, while none of the furanose analogues exhibited any inhibitory effects on HIV-1.The change in potency and specifity of bioactivity by N-alkylation of nitrogen-in-the-ring sugars appears to be correlated with their conformational change.
- Asano, Naoki,Kizu, Haruhisa,Oseki, Kengo,Tomioka, Emiko,Matsui, Katsuhiko,et al.
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p. 2349 - 2356
(2007/10/02)
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- Antiviral compounds
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A method of inhibiting lentivirus is disclosed which comprises mammalian host susceptible to said lentivirus with a virally inhibitory effective amount of an O-acylated derivative of 1,5-dideoxy-1,5-imino-D-glucitol and their N-alkyl, N-acyl and N-aroyl derivatives in which from one to four of the free hydroxyl groups are O-acylated with carboxylic alkanoyl radicals selected from the group consisting of ω,ω,ω-trifluoroalkanoyl having from three to eight carbon atoms, carboxylic cycloalkanoyl groups having from four to eight carbon atoms and carboxylic acyclic alkanoyl groups having from two to ten carbon atoms, wherein the N-aroyl groups contain from 7 to 14 carbon atoms, the N-acyl groups contain from 4 to 8 carbon atoms and the N-alkyl groups contain from 1 to 14 carbon atoms.
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- Process for producing polyhydroxylated piperidines and pyrrolidines and compounds thereof
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A process for converting 1,4- and 1,5-dicarbonyl sugars to pyrrolidine and piperidine amino sugars. Novel compounds resulting from this process are also described.
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- Expeditious synthesis of azasugars by the double reductive amination of dicarbonyl sugars
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Polyhydroxylated pyrrolidines and piperidines were prepared by the double reductive amination of dicarbonyl sugars with primary amines and NaCNBH3 in MeOH. Stereocontrol in these reactions depended on the nature of the amine and dicarbonyl sugar. For example, 5-keto-D-fructose (7) gave three pyrrolidine stereoisomers, with the N-alkylated 2,5-anhydro-2,5-imino-D-glucitol predominating. Under similar reaction conditions with benzhydrylamine, 5-keto-D-glucose (20) afforded a 96:4 mixture of piperidines favoring D-gluco 25A, whereas 5-keto-D-mannose (6) produced a 67:33 mixture enriched in D-manno isomer 40. This method allowed for the direct and relatively short synthesis of 1-deoxynojirimycin (DNJ, 1) and 1-deoxymannojirimycin (DMJ, 5) and N-alkylated derivatives thereof. Similar reactions with O-protected 5-keto-D-glucose derivatives 21 and 22 were less stereoselective and lower yielding.
- Baxter,Reitz
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p. 3175 - 3185
(2007/10/02)
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- 1,5-dideoxy-1,5-imino-D-glucitol derivatives
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O-acylated derivatives of 1,5-dideoxy-1,5-imino-D-glucitol are disclosed that contain an N-alkyl or N-aroyl radical in which from one to four of the free hydroxyl groups are O-acylated with carboxylic alkanoyl radicals selected from the group consisting of ω,ω,ω-trifluoro alkanoyl having from three to eight carbon atoms, carboxylic cycloalkanoyl groups having from four to eight carbon atoms and carboxylic acyclic alkanoyl groups having from two to ten carbon atoms, wherein the N-aroyl radical is selected from the group consisting of p-decylbenzoyl, 3-(p-chlorophenoxy)propanoyl, 2-(acetyloxy)benzoyl, [1,1'-biphenyl]-4-ylcarbonyl, 2-thiopheneacetyl, trans-3-furanacryloyl 3-methoxyphenylacetyl and 3-(trifluoromethyl)benzoyl, and wherein the N-alkyl contains from one to fourteen carbon atoms, provided that when N-alkyl contains from one to five carbon atoms the O-acylated groups are ω,ω,ω-trifluoro alkanoyl or carboxylic cycloalkanoyl.
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- 1,5-dideoxy-1,5-imino-d-glucitol derivatives
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Antiviral O-acylated derivatives of 1,5-dideoxy-1,5-imino-D-glucitol are disclosed that contain an N-alkyl or N-aroyl radical in which from one to four of the free hydroxyl groups are O-acylated with carboxylic alkanoyl radicals selected from the group consisting of ω,ω,ω-trifluoro alkanoyl having from three to eight carbon atoms, carboxylic cycloalkanoyl groups having from four to eight carbon atoms and carboxylic acyclic alkanoyl groups having from two to ten carbon atoms, wherein the N-aroyl radical is selected from the group consisting of p-decylbenzoyl, 3-(p-chlorophenoxy)propanoyl, 2-(acetyloxy)benzoyl, [1,1'-biphenyl]-4-ylcarbonyl, 2-thiopheneacetyl, trans-3-furanacryloyl, 3-methoxyphenylacetyl and 3-(trifluoromethyl)benzoyl, and wherein the N-alkyl contains from one to fourteen carbon atoms, provided that when N-alkyl contains from one to five carbon atoms the O-acylated groups are ω,ω,ω-trifluoro alkanoyl or carboxylic cycloalkanoyl.
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- 1,5-dideoxy-1,5-imino-D-glucitol derivatives
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O-acylated derivatives of 1,5-dideoxy-1,5-imino-D-glucitol and their N-alkyl, N-acyl and N-aryl derivatives in which from one to four of the free hydroxyl groups are acylated with acyl groups having from one to eight carbon atoms and in which the N-alkyl and N-acyl substituents contain from four to fourteen carbon atoms and the N-aryl substituents contain from seven to fourteen carbon atoms are disclosed, provided that when N-aryl is benzyloxycarbonyl, the O-acyl groups contain four to eight carbon atoms.
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