Iminosugars: The Potential of Carbohydrate Analogs

Asano, Naoki

doi:10.1142/9781783267200_0011

Cited by 5 publications

(7 citation statements)

References 73 publications

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“…On the other hand, changes in the configuration of iminosugar stereocenters have often provided unexpected yet promising results [29]. Particularly l-iminosugars, which were non-superimposable mirror images of the corresponding d-iminosugars, showed higher selectivity towards specific enzymes [21,30,31] and an even more interesting pharmacological potential towards several diseases than their d-enantiomers [20,21,[32][33][34]. Among l-iminosugars with a gluco configuration, our recent findings highlighted the potential of l-NBDNJ (the enantiomer of the iminosugar drug d-NBDNJ, Zavesca ® ) as a promising and selective new candidate for the combination therapy of Pompe disease [34].…”

Section: Introductionmentioning

confidence: 99%

N-Nonyloxypentyl-l-Deoxynojirimycin Inhibits Growth, Biofilm Formation and Virulence Factors Expression of Staphylococcus aureus

et al. 2020

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Staphylococcus aureus is one of the major causes of hospital- and community-associated bacterial infections throughout the world, which are difficult to treat due to the rising number of drug-resistant strains. New molecules displaying potent activity against this bacterium are urgently needed. In this study, d- and l-deoxynojirimycin (DNJ) and a small library of their N-alkyl derivatives were screened against S. aureus ATCC 29213, with the aim to identify novel candidates with inhibitory potential. Among them, N-nonyloxypentyl-l-DNJ (l-NPDNJ) proved to be the most active compound against S. aureus ATCC 29213 and its clinical isolates, with the minimum inhibitory concentration (MIC) value of 128 μg/mL. l-NPDNJ also displayed an additive effect with gentamicin and oxacillin against the gentamicin- and methicillin-resistant S. aureus isolate 00717. Sub-MIC values of l-NPDNJ affected S. aureus biofilm development in a dose-dependent manner, inducing a strong reduction in biofilm biomass. Moreover, real-time reverse transcriptase PCR analysis revealed that l-NPDNJ effectively inhibited at sub-MIC values the transcription of the spa, hla, hlb and sea virulence genes, as well as the agrA and saeR response regulator genes.

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Section: Introductionmentioning

confidence: 99%

N-Nonyloxypentyl-l-Deoxynojirimycin Inhibits Growth, Biofilm Formation and Virulence Factors Expression of Staphylococcus aureus

et al. 2020

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“…Furthermore, seven-membered ring iminosugar have shown potential glucosidase inhibition [33,34,35]. Comprehensive studies on iminosugar derivatives can be found in literature reviews [36,37,38,39].…”

Section: Introductionmentioning

confidence: 99%

Iminosugars: Effects of Stereochemistry, Ring Size, and N-Substituents on Glucosidase Activities

2019

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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.

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“…These form, probably, the most important class of carbohydrate mimics reported to date [27,28,29,30]. However, one of the major drawbacks associated with imino analogues of glycosides is their instability caused by the lability of the N , O -acetal function, which prevents their use as biological probes or drug candidates.…”

Section: Introductionmentioning

confidence: 99%

“…Iminosugar-1- C -glycosides are powerful inhibitors of a wide variety of glycosidases [27,28,29,30], and glycosyltransferases down to a femtomolar range [34,35,36]. They may also be employed as pharmacological chaperones to treat deficiencies characterized by improperly folded proteins [37].…”

Section: Introductionmentioning

confidence: 99%

Glycoside Mimics from Glycosylamines: Recent Progress

Nicolas

Martin

2018

Molecules

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Glycosylamines are valuable sugar derivatives that have attracted much attention as synthetic intermediates en route to iminosugar-C-glycosyl compounds. Iminosugars are among the most important glycomimetics reported to date due to their powerful activities as inhibitors of a wide variety of glycosidases and glycosyltransferases, as well as for their use as pharmacological chaperones. As they provide ready access to these important glycoside mimics, we have reviewed the most significant glycosylamine-based methodologies developed to date, with a special emphasis on the literature reported after 2006. The groups of substrates covered include N-alkyl- and N-benzyl-glycosylamines, N-glycosylhydroxylamines, N-(alkoxycarbonyl)-, and N-tert-butanesulfinyl-glycosylamines.

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Iminosugars: The Potential of Carbohydrate Analogs

Cited by 5 publications

References 73 publications

N-Nonyloxypentyl-l-Deoxynojirimycin Inhibits Growth, Biofilm Formation and Virulence Factors Expression of Staphylococcus aureus

N-Nonyloxypentyl-l-Deoxynojirimycin Inhibits Growth, Biofilm Formation and Virulence Factors Expression of Staphylococcus aureus

Iminosugars: Effects of Stereochemistry, Ring Size, and N-Substituents on Glucosidase Activities

Glycoside Mimics from Glycosylamines: Recent Progress

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