Source:http://linkedlifedata.com/resource/pubmed/id/12866083
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
14
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| pubmed:dateCreated |
2003-7-16
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| pubmed:abstractText |
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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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:status |
PubMed-not-MEDLINE
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| pubmed:month |
Jul
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| pubmed:issn |
0947-6539
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:day |
21
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| pubmed:volume |
9
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
3397-414
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| pubmed:dateRevised |
2009-8-4
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| pubmed:year |
2003
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| pubmed:articleTitle |
Highly diastereoselective additions to polyhydroxylated pyrrolidine cyclic imines: ready elaboration of aza-sugar scaffolds to create diverse carbohydrate-processing enzyme probes.
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| pubmed:affiliation |
Dyson Perrins Laboratory, Department of Chemistry, University of Oxford, South Parks Road, Oxford OX1 3QY, UK.
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| pubmed:publicationType |
Journal Article
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