- Tuning the activity of iminosugars: novel N-alkylated deoxynojirimycin derivatives as strong BuChE inhibitors
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We have designed unprecedented cholinesterase inhibitors based on 1-deoxynojirimycin as potential anti-Alzheimer’s agents. Compounds are comprised of three key structural motifs: the iminosugar, for interaction with cholinesterase catalytic anionic site (
- Ahuja-Casarín, Ana I.,Merino-Montiel, Penélope,Vega-Baez, José Luis,Montiel-Smith, Sara,Fernandes, Miguel X.,Lagunes, Irene,Maya, Inés,Padrón, José M.,López, óscar,Fernández-Bola?os, José G.
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p. 138 - 146
(2020/11/27)
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- Design, synthesis, and activity evaluation of novel N-benzyl deoxynojirimycin derivatives for use as α-glucosidase inhibitors
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To obtain α-glucosidase inhibitors with high activity, 19 NB-DNJDs (N-benzyldeoxynojirimycin derivatives) were designed and synthesized. The results indicated that the 19 NBDNJDs displayed different inhibitory activities towards α-glucosidase in vitro. Compound 18a (1- (4-hydroxy-3-methoxybenzyl)-2-(hydroxymethyl) piperidine-3,4,5-triol) showed the highest activity, with an IC50 value of 0.207 ± 0.11 mM, followed by 18b (1-(3-bromo-4-hydroxy-5- methoxybenzyl)-2-(hydroxymethyl) piperidine-3,4,5-triol, IC50: 0.276 ± 0.13 mM). Both IC50 values of 18a and 18b were significantly lower than that of acarbose (IC50: 0.353 ± 0.09 mM). According to the structure-activity analysis, substitution of the benzyl and bromine groups on the benzene ring decreased the inhibition activity, while methoxy and hydroxyl group substitution increased the activity, especially with the hydroxyl group substitution. Molecular docking results showed that three hydrogen bonds were formed between compound 18a and amino acids in the active site of α- glucosidase. Additionally, an arene-arene interaction was also modelled between the phenyl ring of compound 18a and Arg 315. The three hydrogen bonds and the arene-arene interaction resulted in a low binding energy (-5.8 kcal/mol) and gave 18a a higher inhibition activity. Consequently, compound 18a is a promising candidate as a new α-glucosidase inhibitor for the treatment of type II diabetes.
- Zeng, Fanxin,Yin, Zhongping,Chen, Jiguang,Nie, Xuliang,Lin, Ping,Lu, Tao,Wang, Meng,Peng, Dayong
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- Concise synthesis of 1-epi-castanospermine
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1-epi-Castanospermine (5) was synthesized from readily available 2,3,4,6-tetra-O-benzyl-1-deoxynojirimycin (11) in 9 steps and 21% overall yield, with selective debenzylation, Barbier reaction and reductive amination as the main reaction steps.
- Cheng, Bin,Li, Yi-Xian,Jia, Yue-Mei,Yu, Chu-Yi
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supporting information
p. 1688 - 1692
(2017/07/27)
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- Structure–Activity Studies of N-Butyl-1-deoxynojirimycin (NB-DNJ) Analogues: Discovery of Potent and Selective Aminocyclopentitol Inhibitors of GBA1 and GBA2
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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.
- Gu, Xingxian,Gupta, Vijayalaxmi,Yang, Yan,Zhu, Jin-Yi,Carlson, Erick J.,Kingsley, Carolyn,Tash, Joseph S.,Sch?nbrunn, Ernst,Hawkinson, Jon,Georg, Gunda I.
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p. 1977 - 1984
(2017/11/30)
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- Selenoureido-iminosugars: A new family of multitarget drugs
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Herein we report the synthesis of N-alkylated deoxynojirimycin derivatives decorated with a selenoureido motif at the hydrocarbon tether as an example of unprecedented multitarget agents. Title compounds were designed as dual drugs for tackling simultaneously the Gaucher disease (by selective inhibition of β-glucosidase, Ki= 1.6–5.5 μM, with improved potency and selectivity compared to deoxynojirimycin) and its neurological complications (by inhibiting AChE, Kiup to 5.8 μM). Moreover, an excellent mimicry of the selenoenzyme glutathione peroxidase was also found for the catalytic scavenging of H2O2(Kcat/Kuncatup to 640) using PhSH as a cofactor, with improved activity compared to known positive controls, like (PhSe)2and ebselen; therefore, such compounds are also excellent scavengers of peroxides, an example of reactive oxygen species present at high concentrations in patients of Gaucher disease and neurological disorders.
- Olsen, Jacob Ingemar,Plata, Gabriela B.,Padrón, José M.,López, óscar,Bols, Mikael,Fernández-Bola?os, José G.
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p. 155 - 160
(2016/08/01)
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- SYNTHESIS OF AN AZASUGAR AND THE INTERMEDIATES THEREOF
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Process for the preparation of intermediates useful in the synthesis of miglustat and their use in its manufacture.
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Paragraph 0050; 0053; 0054
(2016/12/07)
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- High sugar composition for treatment and method
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The invention relates to the compounds of formula (I) or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof The pharmaceutical compositions comprising an effective amount of compounds of formula (I), and methods for the treatment of hyperglycemia may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of insulin resistance, diabetes mellitus, diabetes insipidus, type 1 diabetes, type 2 diabetes, microvascular complications, macrovascular complications, lipid disorders, prediabetes, obesity, arrhythmia, myocardial infarction, stroke, neuropathy, renal complications, hypertriglyceridemia, cardiovascular complications, and post prandial hyperglycemia.
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Paragraph 0095; 0096; 0099; 0100
(2017/03/25)
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- Compositions and methods for the treatment of hyperglycemia
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The invention relates to the compounds of formula I or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I, and methods for the treatment of hyperglycemia may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of insulin resistance, diabetes mellitus, diabetes insipidus, type 1 diabetes, type 2 diabetes, microvascular complications, macrovascular complications, lipid disorders, prediabetes, obesity, arrhythmia, myocardial infarction, stroke, neuropathy, renal complications, hypertriglyceridemia, cardiovascular complications, and post prandial hyperglycemia.
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Page/Page column 26
(2015/10/28)
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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 0069
(2014/08/06)
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- Amphiphilic 1-deoxynojirimycin derivatives through click strategies for chemical chaperoning in N370S gaucher cells
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In Gaucher disease (GD), mutant β-glucocerebrosidases (β-GCase) that are misfolded are recognized by the quality control machinery of the endoplasmic reticulum (ER) and degraded proteolytically. Hydrophobic iminosugars can be used as pharmacological chaperones to provide an improvement in the folding of the enzyme and promote trafficking from the ER. We have developed here an efficient click procedure to tether hydrophobic substituents to N-azidopropyl-1-deoxynojirimycin. A set of 14 original iminosugars was designed and evaluated for inhibition of commercially available glucosidases. Most of the compounds were micromolar inhibitors of those enzymes. In vitro inhibition assays with the N370S β-GCase revealed that the sublibrary containing the derivatives with aromatic aglycons displayed the highest inhibitory potency. Chaperone activity of the whole set of synthetic compounds was also explored in mutant Gaucher cells. The most active compound gave a nearly 2-fold increase in enzyme activity at 20 μM, a significantly higher value than the 1.33-fold recorded for the reference compound N-nonyl-1-deoxynojirimycin (N-nonyl-DNJ). As previously reported with bicyclic sp2-iminosugars (Luan, Z.; Higaki, K.; Aguilar-Moncayo, M.; Ninomiya, H.; Ohno, K.; Garcia-Moreno, M. I.; Ortiz Mellet, C.; Garcia Fernandez, J. M.; Suzuki, Y. ChemBioChem 2009, 10, 2780), in vitro inhibition of β-GCase measured for the compounds did not correlate with the cellular chaperone activity. The potency of new iminosugar chaperones is therefore not predictable from structureactivity relationships studies based on the in vitro β-GCase inhibition. (Figure presented)
- Diot, Jennifer D.,Moreno, Isabel Garcia,Twigg, Gabriele,Mellet, Carmen Ortiz,Haupt, Karsten,Butters, Terry D.,Kovensky, Jose,Gouin, Sebastien G.
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scheme or table
p. 7757 - 7768
(2011/12/03)
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- Multivalent iminosugars to modulate affinity and selectivity for glycosidases
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A series of mono-, di- and tri-valent iminosugars based on oligoethylene scaffolds and N-substituted deoxynojirymicin epitopes have been synthesized by "click chemistry" to study the effect of multivalency on glycosidase inhibition. Biological evaluation evidenced differences in the inhibition trends as a function of the enzyme nature. The results demonstrate that multivalency can be used in some case to modulate both the affinity and the selectivity of glycosidase inhibition.
- Diot, Jennifer,Garcia-Moreno, M. Isabel,Gouin, Sebastien G.,Mellet, Carmen Ortiz,Haupt, Karsten,Kovensky, Jose
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scheme or table
p. 357 - 363
(2009/03/11)
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- Large-scale synthesis of the glucosylceramide synthase inhibitor N-[5-(adamantan-1-yl-methoxy)-pentyl]-1-deoxynojirimycin
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A synthetic route for the preparation of glucosylceramide synthase inhibitor N-[5-(adamantan-1-yl-methoxy)-pentyl]-1-deoxynojirimycin methanesulfonic acid salt (AMP-DNM) has been developed. Herein we report the development and optimization of this synthetic route from its initial version in an academic research laboratory at milligram-scale to the final optimized route that was implemented in a cGMP miniplant on kilogram-scale. The definitive route starts with the separate synthesis of building blocks 2,3,4,6-tetra-O- benzyl-1-deoxynojirimycin and 5-(adamantan-1-ylmethoxy)-pentanal. The aldehyde was synthesized from 1,5-pentanediol in five steps and 45% overall yield. Protected 1-deoxynojirimycin was prepared by a successive hemiacetal reduction/Swern oxidation/double reductive amination sequence of 2,3,4,5-tetra-O-benzyl-D-glucopyranose in 52% overall yield. Reductive amination of the two building blocks produced the benzylprotected penultimate that was isolated as its crystalline (+)DTTA salt in 68% yield. Hydrogenolysis of the penultimate and crystallization of the end product as its methanesulfonic acid salt produced AMP-DNM in 76% yield with a purity of >99.5%. The described route enables the production of multikilogram amounts of inhibitor AMP-DNM as a stable crystalline solid with high purity under cGMP control.
- Wennekes, Tom,Lang, Bemhard,Leeman, Michel,Van Der Marel, Gijsbert A.,Smits, Elly,Weber, Matthias,Van Wiltenburg, Jim,Wolberg, Michael,Aerts, Johannes M.F.G.,Overkleeft, Herman S.
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p. 414 - 423
(2013/01/03)
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- Development of adamantan-1-yl-methoxy-functionalized 1-deoxynojirimycin derivatives as selective inhibitors of glucosylceramide metabolism in man
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(Chemical Equation Presented) In this article, we present a straightforward synthesis of adamantan-1-yl-methoxy-functionalized 1-deoxynojirimycin derivatives. The used synthetic routes are flexible and can be used to create a wide variety of lipophilic mo
- Wennekes, Tom,Van Den Berg, Richard J. B. H. N.,Donker, Wilma,Van Der Marel, Gijsbert A.,Strijland, Anneke,Aerts, Johannes M. F. G.,Overkleeft, Herman S.
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p. 1088 - 1097
(2007/10/03)
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- Cis-stereoselective SmI2-promoted reductive coupling of keto-nitrones: First synthesis of 1-epitrehazolamine
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An expeditious synthesis of 1-epitrehazolamine is presented from readily available 2,3,4,6-tetra-O-benzyl-D-glucose. The key step involves a samarium diiodide-promoted reductive cyclization of a masked keto-nitrone to form a fivemembered ring aminocyclito
- Masson, Geraldine,Philouze, Christian,Py, Sandrine
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p. 2067 - 2069
(2007/10/03)
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- Intramolecular Tishchenko reactions of protected hexos-5-uloses: A novel and efficient synthesis of L-idose and L-altrose
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Protected t-butyl esters of aldonic acids with the rare L-ido and L- altro configuration can be effectively obtained by a diastereoselective Tishchenko reaction of hexos-5-uloses induced by t-BuOSmI2. These compounds can be easily converted int
- Adinolfi,Barone,De Lorenzo,Iadonisi
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p. 336 - 338
(2007/10/03)
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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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- A Highly Efficient Pinacol Coupling Approach to Trehazolamine Starting from D-Glucose
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A short and very efficient synthesis of trehazolamine (3), the aglycon of the potent trehalase inhibitor trehazolin (2), has been achieved starting from D-glucose. The key transformation in this approach is a high-yielding two-step, one-pot sequence consisting of a Swern oxidation of a 1,5-diol followed by a reductive carbocyclization of the resultant 1,5-dicarbonyl compound promoted by samarium diiodide. The overall yield of 3 is 39% over nine steps from 2,3,4,6-tetra-O-benzyl-D-glucose (5). An even shorter synthesis of 30, a diastereoisomeric analogue of 3, is also described starting from 5. The key transformation in this second route is a highly stereoselective ketone oxime ether reductive carbocyclization promoted also by samarium diiodide. The overall yield of 30 is 57% over four steps from 5.
- De Gracia, Isabel Storch,Dietrich, Hansjoerg,Bobo, Sofia,Chiara, Jose Luis
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p. 5883 - 5889
(2007/10/03)
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