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.
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.
Choubdar
Niloufar
N
Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
Bhat
Ramakrishna G
RG
Stubbs
Keith A
KA
Yuzwa
Scott
S
Pinto
B Mario
BM
D000118:Acetylglucosaminidase / Q000037:antagonists & inhibitors*; D000577:Amides / Q000138:chemical synthesis*; D000606:Amino Sugars / Q000138:chemical synthesis*; D001386:Azides / Q000138:chemical synthesis*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors*; D006801:Humans; D013402:Sugar Alcohols / Q000138:chemical synthesis*; D013431:Sulfates / Q000138:chemical synthesis*; D001619:beta-N-Acetylhexosaminidases / Q000037:antagonists & inhibitors*
D000577:Amides; D000606:Amino Sugars; D001386:Azides; D004791:Enzyme Inhibitors; D013402:Sugar Alcohols; D013431:Sulfates; C427963:salacinol; D006026:Glycoside Hydrolases; C110628:hexosaminidase C; D000118:Acetylglucosaminidase; D001619:beta-N-Acetylhexosaminidases