Synthesis and Evaluation of Homoaza Sugars as Glycosidase Inhibitors

Wong, Chi‐Huey; Provencher, Louis; Porco, John A.; Jung, Sang‐Hun; Wang, Yi-Fong; Chen, Lih-Ren; Wang, Ruo; Steensma, Darryl H.

doi:10.1021/jo00111a007

Cited by 155 publications

(65 citation statements)

References 4 publications

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“…Likewise, reductive amination of octyl aldehyde and DNJ gave N-(n-octyl)deoxynojirimycin. Compound 6 was generated by the treatment of N-nonyl-2,5-anhydro-imino-D-glucitol 2 and 2-methoxypropene in the presence of p-toluene sulfonic acid (catalytic amount) (26,27). Structural characterization was accomplished by 1 H-NMR, 13 C-NMR, and high-resolution MS (see Supporting Text, which is published as supporting information on the PNAS web site, www.pnas.org).…”

Section: ␤-Glu Inhibitors and Related Molecules To Probe The Requiremmentioning

confidence: 99%

Chemical chaperones increase the cellular activity of N370S β-glucosidase: A therapeutic strategy for Gaucher disease

Sawkar

Cheng

Beutler

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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484

455

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Gaucher disease is a lysosomal storage disorder caused by deficient lysosomal ␤-glucosidase (␤-Glu) activity. A marked decrease in enzyme activity results in progressive accumulation of the substrate (glucosylceramide) in macrophages, leading to hepatosplenomegaly, anemia, skeletal lesions, and sometimes CNS involvement. Enzyme replacement therapy for Gaucher disease is costly and relatively ineffective for CNS involvement. Chemical chaperones have been shown to stabilize various proteins against misfolding, increasing proper trafficking from the endoplasmic reticulum. We report herein that the addition of subinhibitory concentrations (10 M) of N-(n-nonyl)deoxynojirimycin (NN-DNJ) to a fibroblast culture medium for 9 days leads to a 2-fold increase in the activity of N370S ␤-Glu, the most common mutation causing Gaucher disease. Moreover, the increased activity persists for at least 6 days after the withdrawal of the putative chaperone. The NN-DNJ chaperone also increases WT ␤-Glu activity, but not that of L444P, a less prevalent Gaucher disease variant. Incubation of isolated soluble WT enzyme with NN-DNJ reveals that ␤-Glu is stabilized against heat denaturation in a dose-dependent fashion. We propose that NN-DNJ chaperones ␤-Glu folding at neutral pH, thus allowing the stabilized enzyme to transit from the endoplasmic reticulum to the Golgi, enabling proper trafficking to the lysosome. Clinical data suggest that a modest increase in ␤-Glu activity may be sufficient to achieve a therapeutic effect.

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Section: ␤-Glu Inhibitors and Related Molecules To Probe The Requiremmentioning

confidence: 99%

Chemical chaperones increase the cellular activity of N370S β-glucosidase: A therapeutic strategy for Gaucher disease

Sawkar

Cheng

Beutler

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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484

455

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“…Indeed, previous studies have established very similar inhibitory potency for the methyl threitol 33 a (K i 5.5 mm). [43] It should be noted that the results obtained here support previous findings that pyrrolidine aza-sugars are good inhibitors of a-l-rhamnosidase [11,43] (for example, l-swainsonine and DRAM, two of the most powerful known pyrrolidine inhibitors display K i 0.45 and 1.0 mm, respectively) [11] and typically much better than piperidine analogues of l-rhamnose, [6,44] possibly by virtue of the ability of envelope conformations of pyrrolidines to mimic boat, [45] envelope, [46] or half chair [47] transition state conformations in the rhamnosidase mechanism.…”

Section: Synthesis Of Anisomycin Analoguesmentioning

confidence: 99%

Highly Diastereoselective Additions to Polyhydroxylated Pyrrolidine Cyclic Imines: Ready Elaboration of Aza‐Sugar Scaffolds To Create Diverse Carbohydrate‐Processing Enzyme Probes

Chapman

Courtney

Hay

et al. 2003

Chemistry A European J

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Representative diastereomeric, erythritol and threitol polyhydroxylated pyrrolidine imine scaffolds have been rapidly elaborated to diversely functionalized aza-sugars through highly diastereoselective organometallic (RM) additions (R=Me, Et, allyl, hexenyl, Ph, Bn, pMeO-Bn). The yields for these additions have all been substantially enhanced from previously optimised levels (<58 %) for normal additions using a reverse addition procedure (e.g. R=Ph; 44 % normal mode --> 78 % reverse mode). The high diastereoselectivities (>98 % de for all except R=Me) are consistent with additions that are controlled by the configuration of the C-2 centre adjacent to the azomethine imine carbon and the conformation of the pyrrolidine imine. The high potential of this method was demonstrated by concise syntheses of 1-epi- and 2-epi-desacetylanisomycins. In addition, the late stage addition of hydrophobic substituents, which this imine addition methodology allows, enabled the preparation of novel aza-sugars with enhanced inhibitory potential. This was highlighted by the screening of a representative selection of these "hydrophobically-modified" aza-sugars against a diverse panel of 12 non-mammalian and human carbohydrate-processing enzymes. This identified a novel nanomolar alpha-galactosidase inhibitor (IC(50)=250 nM) and a novel highly selective glucosylceramide synthase inhibitor (IC(50)=52 microM, no alpha-glucosidase inhibition at 1 mM). Furthermore, analysis of the structure-activity relationships of racemic series of inhibitors allowed some validation of Fleet's mirror-image enzyme active site postulate.

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“…1-Deoxy-or homo-L L-fuco-nojirimycin derivatives L L-1a, L L-1c are nanomolar inhibitors of a-L L-fucosidase from various sources. [4][5][6][7][8] Amino-L L-lyxose sugar 2b 9,10 and its 1-deoxy-derivative 2a [9][10][11] are likewise potent inhibitors of the a-L L-fucosidase of bovine kidney; the a-homo derivative 2c has also a K i value in the nanomolar range. 12 We describe the asymmetric synthesis and the enzymatic evaluation of the L L-fuco-nojirimycin L L-1b, which is a new analogue of nojirimycin and which looks like a promising fucosidase inhibitor.…”

mentioning

confidence: 99%

Asymmetric synthesis of the l-fuco-nojirimycin, a nanomolar α-l-fucosidase inhibitor

Dubernet

Defoin

Tarnus

2006

Bioorganic & Medicinal Chemistry Letters

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Synthesis and Evaluation of Homoaza Sugars as Glycosidase Inhibitors

Cited by 155 publications

References 4 publications

Chemical chaperones increase the cellular activity of N370S β-glucosidase: A therapeutic strategy for Gaucher disease

Chemical chaperones increase the cellular activity of N370S β-glucosidase: A therapeutic strategy for Gaucher disease

Highly Diastereoselective Additions to Polyhydroxylated Pyrrolidine Cyclic Imines: Ready Elaboration of Aza‐Sugar Scaffolds To Create Diverse Carbohydrate‐Processing Enzyme Probes

Asymmetric synthesis of the l-fuco-nojirimycin, a nanomolar α-l-fucosidase inhibitor

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