Document Detail

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.
MedLine Citation:
PMID:  18358456     Owner:  NLM     Status:  MEDLINE    
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.
Niloufar Choubdar; Ramakrishna G Bhat; Keith A Stubbs; Scott Yuzwa; B Mario Pinto
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-03-07
Journal Detail:
Title:  Carbohydrate research     Volume:  343     ISSN:  0008-6215     ISO Abbreviation:  Carbohydr. Res.     Publication Date:  2008 Jul 
Date Detail:
Created Date:  2008-06-18     Completed Date:  2008-09-11     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0043535     Medline TA:  Carbohydr Res     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  1766-77     Citation Subset:  IM    
Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
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MeSH Terms
Acetylglucosaminidase / antagonists & inhibitors*
Amides / chemical synthesis*
Amino Sugars / chemical synthesis*
Azides / chemical synthesis*
Enzyme Inhibitors / chemical synthesis*,  pharmacology
Glycoside Hydrolases / antagonists & inhibitors*
Sugar Alcohols / chemical synthesis*
Sulfates / chemical synthesis*
beta-N-Acetylhexosaminidases / antagonists & inhibitors*
Reg. No./Substance:
0/Amides; 0/Amino Sugars; 0/Azides; 0/Enzyme Inhibitors; 0/Sugar Alcohols; 0/Sulfates; 0/salacinol; EC 3.2.1.-/Glycoside Hydrolases; EC C; EC; EC

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