19130-96-2Relevant academic research and scientific papers
1,3-Oxazine as a chiral building block used in the total synthesis of (+)-1-deoxynojirimycin and (2R,5R)-dihydroxymethyl-(3R,4R)-dihydroxypyrrolidine
Park, Seok-Hwi,Kim, Ji-Yeon,Kim, Jin-Seok,Jung, Changyoung,Song, Dong-Keun,Ham, Won-Hun
, p. 657 - 661 (2015)
Concise and stereocontrolled syntheses of (+)-1-deoxynojirimycin and (2R,5R)-dihydroxymethyl-(3R,4R)-dihydroxypyrrolidine [(+)-DMDP] were achieved via a diastereomerically enriched oxazine intermediate. The key strategies include the use of 1,3-oxazine as a chiral building block and diastereoselective nucleophilic addition to an aldehyde. Starting from readily available (R)-methyl 2-benzamido-3-((tert-butyldimethylsilyl)oxy)propanoate, (+)-1-deoxynojirimycin was synthesized in 11 steps and 26.2% overall yield while (+)-DMDP was synthesized in 11 steps and 27.1% overall yield, respectively.
A short and practical synthesis of 1-deoxynojirimycin
Behling,Farid,Medich,Scaros,Prunier,Weier,Khanna
, p. 1383 - 1386 (1991)
The potent glucosidase inhibitor 1-deoxynojirimycin was synthesized from L-sorbose using a short synthesis and only one protecting group. The last step, which constituted the removal of an acetonide protecting group and an intramolecular reductive amination, was accomplished on an acidic ion-exchange resin. This provided a synthesis capable of being operated on a multi-kilogram scale.
A fluorescence study of isofagomine protonation in β-glucosidase
Lindb?ck, Emil,Laursen, Bo Wegge,Poulsen, Jens Christian Navarro,Kils?, Kristine,Pedersen, Christian Marcus,Bols, Mikael
, p. 6562 - 6566 (2015)
N-(10-Chloro-9-anthracenemethyl)isofagomine 5 and N-(10-chloro-9-anthracenemethyl)-1-deoxynojirimycin 6 were prepared, and their inhibition of almond β-glucosidase was measured. The isofagomine derivative 5 was found to be a potent inhibitor, while the 1-deoxynojirimycin derivative 6 displayed no inhibition at the concentrations investigated. Fluorescence spectroscopy of 5 with almond β-glucosidase at different pH values showed that the inhibitor nitrogen is not protonated when bound to the enzyme. Analysis of pH inhibition data confirmed that 5 binds as the amine to the enzyme's unprotonated dicarboxylate form. This is a radically different binding mode than has been observed with isofagomine and other iminosugars in the literature.
Isotope edited NMR studies of glycosidases: Design and synthesis of a novel glycosidase inhibitor
Hines, Jennifer V.,Chang, Heesun,Gerdeman, Melinda S.,Warn, Dana E.
, p. 1255 - 1260 (1999)
N-13C-methyl-deoxynojirimycin was synthesized and used in isotope- edited NMR studies to probe the binding site of an α-glucosidase. Results from this analysis led to the design and preparation of a novel α- glucosidase inhibitor, N-glycyl deoxynojirimycin.
Design, synthesis, and activity evaluation of novel N-benzyl deoxynojirimycin derivatives for use as α-glucosidase inhibitors
Zeng, Fanxin,Yin, Zhongping,Chen, Jiguang,Nie, Xuliang,Lin, Ping,Lu, Tao,Wang, Meng,Peng, Dayong
, (2019/09/19)
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.
Asymmetric total syntheses of (+)-2,5-dideoxy-2,5-imino-D-glucitol [(+)-DGDP] and (?)-1-deoxymannojirimycin [(?)-DMJ] via an extended chiral 1,3-oxazine
Myeong, In-Soo,Jung, Changyoung,Kim, Ji-Yeon,Park, Seok-Hwi,Ham, Won-Hun
, p. 2422 - 2425 (2018/05/25)
The asymmetric total syntheses of (+)-2,5-dideoxy-2,5-imino-D-glucitol [(+)-DGDP] 1 and (?)-1-deoxymannojirimycin [(?)-DMJ] 2 were achieved using an extended chiral 1,3-oxazine. The key synthetic strategies included extension of the chirality of anti,syn-oxazine 3 using diastereoselective dihydroxylation, and piperidine and pyrrolidine ring formation. Starting from readily available anti,syn-oxazine 3, (+)-DGDP 1 was synthesized in 5 steps with 31.6% overall yield and (?)-DMJ 2 was synthesized in 4 steps with 60.6% overall yield.
Synthesis of 1-deoxynojirimycin: Exploration of optimised conditions for reductive amidation and separation of epimers
Iftikhar, Mehwish,Wang, Lin,Fang, Zhijie
, p. 460 - 464 (2017/08/18)
1-Deoxynojirimycin (DNJ), which has importance with respect to sugar processing enzymes, is a synthetic target for chemists. A key step in the synthesis of DNJ is the preparation of 2,3,4,6-tetra-O-benzyl-D-glucono-δ-lactam. By varying reaction parameters such as temperature, solvent and reducing reagent, improvements on previous methods are described. A novel approach for the synthesis of 2,3,4,6-tetra-O-benzyl-5-dehydro-5-deoxo-D-gluconamide has been developed by using PCC as an oxidising agent. Separation of epimers permitted DNJ to be obtained in 85% yield after reduction and hydrogenolysis steps.
A Fluorescence Polarization Activity-Based Protein Profiling Assay in the Discovery of Potent, Selective Inhibitors for Human Nonlysosomal Glucosylceramidase
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.
supporting information, p. 14192 - 14197 (2017/10/17)
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.
Conformational Behaviour of Azasugars Based on Mannuronic Acid
van Rijssel, Erwin R.,Janssen, Antonius P. A.,Males, Alexandra,Davies, Gideon J.,van der Marel, Gijsbert A.,Overkleeft, Herman S.,Codée, Jeroen D. C.
, p. 1297 - 1304 (2017/07/07)
A set of mannuronic-acid-based iminosugars, consisting of the C-5-carboxylic acid, methyl ester and amide analogues of 1deoxymannorjirimicin (DMJ), was synthesised and their pH-dependent conformational behaviour was studied. Under acidic conditions the methyl ester and the carboxylic acid adopted an “inverted” 1C4 chair conformation as opposed to the “normal” 4C1 chair at basic pH. This conformational change is explained in terms of the stereoelectronic effects of the ring substituents and it parallels the behaviour of the mannuronic acid ester oxocarbenium ion. Because of this solution-phase behaviour, the mannuronic acid ester azasugar was examined as an inhibitor for a Caulobacter GH47 mannosidase that hydrolyses its substrates by way of a reaction itinerary that proceeds through a 3H4 transition state. No binding was observed for the mannuronic acid ester azasugar, but sub-atomic resolution data were obtained for the DMJ?CkGH47 complex, showing two conformations—3S1 and 1C4—for the DMJ inhibitor.
Selenoureido-iminosugars: A new family of multitarget drugs
Olsen, Jacob Ingemar,Plata, Gabriela B.,Padrón, José M.,López, óscar,Bols, Mikael,Fernández-Bola?os, José G.
, p. 155 - 160 (2016/08/01)
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.
