The Structural Basis of Glycosidase Inhibition by Five‐Membered Iminocyclitols: The Clan A Glycoside Hydrolase Endoglycoceramidase as a Model System

Caines, M.E.C.; Hancock, Susan M.; Tarling, Chris A.; Wrodnigg, Tanja; Stick, Robert V.; Stütz, Arnold; Vasella, Andrea; Withers, Stephen G.; Strynadka, N.C.J.

doi:10.1002/anie.200700268

Cited by 40 publications

(21 citation statements)

References 27 publications

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“…Aza-sugars (also known as imino-sugars) are mimetics of native sugars whereby the ring oxygen is replaced by a nitrogen atom. Due to their structural similarity to native carbohydrates, aza-sugars are able to act as glycosidase inhibitors and therefore have enormous therapeutic potential in the treatment of a variety of diseases including viral infection, bacterial infection, lysosomal storage disorders, cancer and diabetes [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. Indeed, the use of Zavesca ® for the treatment of Gaucher’s disease marked the launch of the first aza-sugar medication [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Protecting-Group-Free Synthesis of 2-Deoxy-Aza-Sugars

et al. 2009

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The protecting-group-free asymmetric synthesis of 1,2,4-trideoxy-1,4-imino-L-xylitol is readily achieved in five steps from 2-deoxy-D-ribose and with an overall yield of 48%. Key in this synthesis is the application of our recently developed Vasella-reductive amination and carbamate annulation methodologies to the synthesis of 2-deoxy-aza-sugars. The carbamate annulation occurred with excellent yield and diastereoselectively (>20:1 d.r.), in favour of the 3,4-cis isomer.

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Section: Introductionmentioning

confidence: 99%

Protecting-Group-Free Synthesis of 2-Deoxy-Aza-Sugars

et al. 2009

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“…The biological activities of iminocyclitols are due to the structural similarity of the corresponding protonated compounds under physiological conditions with the flattened half‐chair conformation found for the transition structures involved in the mechanism of glycosidases (Figure 1). 12 In the particular case of the N ‐acetyl‐β‐hexosaminidases, important enzymes involved in osteoarthritis, the participation of the neighboring C‐2 acetamido group of the substrate has been suggested 13. Investigating this hypothesis, Wong and co‐workers14 found that N ‐acetyl‐2‐(aminomethyl)iminocyclitol 2 and its structural analogues are potent inhibitors of N ‐acetyl‐β‐hexosaminidases, and hence are expected to have potential as chondrotherapeutic agents 15.…”

Section: Introductionmentioning

confidence: 99%

Nucleophilic Additions to Cyclic Nitrones en Route to Iminocyclitols – Total Syntheses of DMDP, 6‐deoxy‐DMDP, DAB‐1, CYB‐3, Nectrisine, and Radicamine B

et al. 2008

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Highly diastereoselective nucleophilic additions to cyclic nitrones derived from L-malic acid and D-arabinose have been used for the construction of enantiomerically pure polyhydroxylated pyrrolidines. The synthetic strategy adopted was based on an oxidation/reduction protocol involving hydroxylamine/nitrone pairs and demonstrates the use of reagent-and substrate-derived stereocontrol. In most cases reactions took place with total diastereoselectivity and in quantitative yield, with no purification being necessary. By this strategy, 2-(hydroxymethyl)-, 2-(aminomethyl)-, and 2-aryl-

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“…In this context, the first X-ray crystal structure of a pyrrolidine imino sugar complexed with a b-glycosidase was reported in 2007. 8 In a recent work, 9 L-DMDP 1 and L-homoDMDP 2 ( Fig. 1), the L-enantiomers of DMDP and homoDMDP, have been synthesized via sugar-derived cyclic nitrones as well as 3-deoxy-3-fluoro derivatives.…”

Section: Polyhydroxylated Pyrrolidinesmentioning

confidence: 99%