| Synthesis of 2-amido, 2-amino, and 2-azido derivatives of the nitrogen analogue of the naturally occurring glycosidase inhibitor salacinol and their inhibitory activities against O-GlcNAcase and NagZ enzymes. | |
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MedLine Citation:
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PMID: 18358456 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Seven 2-substituted derivatives of the nitrogen analogue of salacinol, a naturally occurring glycosidase inhibitor, were synthesized for structure-activity studies with hexosaminidase enzymes. The target zwitterionic compounds were synthesized by means of nucleophilic attack of the 2-azido-1,4-dideoxy-1,4-imino-D-arabinitol at the least hindered carbon atom of 2,4-O-benzylidene-L-erythritol-1,3-cyclic sulfate. Hydrogenation of the azido zwitterionic compound in methanol resulted in the reduction of the azide and subsequent methylation of the resulting amine in one pot. A similar reaction, with ethanol as the solvent, gave the N-ethyl derivative. The 2-amino analogues were finally obtained by the reduction of the azide function using triphenylphosphine. Acylation of the amine using acetic, propionic, or valeric anhydride afforded the corresponding 2-amido derivatives. Deprotection of the acylated, coupled products using 80% trifluoroacetic acid proceeded smoothly. Unlike their sulfonium ion counterparts, these compounds were stable and did not undergo ring opening. We also report the synthesis of the parent nitrogen heterocycles, N-Boc-1,2,4-trideoxy-2-amino-1,4-imino-D-arabinitol, and 1,2,4-trideoxy-2-acetamido-1,4-imino-D-arabinitol and its corresponding N-Boc protected compound. The 2-substituted analogues and the parent iminoalditol showed marginal activity (<33% at 250 microM) against human O-GlcNAcase and Vibrio cholerae NagZ enzymes. |
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Authors:
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Niloufar Choubdar; Ramakrishna G Bhat; Keith A Stubbs; Scott Yuzwa; B Mario Pinto |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2008-03-07 |
Journal Detail:
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Title: Carbohydrate research Volume: 343 ISSN: 0008-6215 ISO Abbreviation: Carbohydr. Res. Publication Date: 2008 Jul |
Date Detail:
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Created Date: 2008-06-18 Completed Date: 2008-09-11 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0043535 Medline TA: Carbohydr Res Country: Netherlands |
Other Details:
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Languages: eng Pagination: 1766-77 Citation Subset: IM |
Affiliation:
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Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Acetylglucosaminidase
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antagonists & inhibitors* Amides / chemical synthesis* Amino Sugars / chemical synthesis* Azides / chemical synthesis* Enzyme Inhibitors / chemical synthesis*, pharmacology Glycoside Hydrolases / antagonists & inhibitors* Humans Sugar Alcohols / chemical synthesis* Sulfates / chemical synthesis* beta-N-Acetylhexosaminidases / antagonists & inhibitors* |
| Chemical | |
Reg. No./Substance:
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0/Amides; 0/Amino Sugars; 0/Azides; 0/Enzyme Inhibitors; 0/Sugar Alcohols; 0/Sulfates; 0/salacinol; EC 3.2.1.-/Glycoside Hydrolases; EC 3.2.1.50/hexosaminidase C; EC 3.2.1.52/Acetylglucosaminidase; EC 3.2.1.52/beta-N-Acetylhexosaminidases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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