35237-61-7

Upstream product

• 5432-46-2 1,3,4,6-tetra-O-acetyl-D-glucosamine hydrochloride 
• 62-74-8 sodium fluoroacetate 
• 144-49-0 Fluoroacetic acid 

Relevant academic research and scientific papers

Probing synergy between two catalytic strategies in the glycoside hydrolase O-GlcNAcase using multiple linear free energy relationships

Human O-GlcNAcase plays an important role in regulating the post-translational modification of serine and threonine residues with β-O-linked N-acetylglucosamine monosaccharide unit (O-GlcNAc). The mechanism of O-GlcNAcase involves nucleophilic participation of the 2-acetamido group of the substrate to displace a glycosidically linked leaving group. The tolerance of this enzyme for variation in substrate structure has enabled us to characterize O-GlcNAcase transition states using several series of substrates to generate multiple simultaneous free-energy relationships. Patterns revealing changes in mechanism, transition state, and rate-determining step upon concomitant variation of both nucleophilic strength and leaving group abilities are observed. The observed changes in mechanism reflect the roles played by the enzymic general acid and the catalytic nucleophile. Significantly, these results illustrate how the enzyme synergistically harnesses both modes of catalysis; a feature that eludes many small molecule models of catalysis. These studies also suggest the kinetic significance of an oxocarbenium ion intermediate in the O-GlcNAcase-catalyzed hydrolysis of glucosaminides, probing the limits of what may be learned using nonatomistic investigations of enzymic transition-state structure and offering general insights into how the superfamily of retaining glycoside hydrolases act as efficient catalysts.

SELECTIVE GLYCOSIDASE INHIBITORS AND USES THEREOF

The invention provides compounds of formula (I) for selectively inhibiting glycosidases, prodrugs of the compounds, and pharmaceutical compositions including the compounds or prodrugs of the compounds The invention also provides methods of treating diseas

Haloacetamido analogues of 2-amino-2-deoxy-d-glucose and 2-amino-2-deoxy-d-galactose. Syntheses and effects on the Friend murine erythroleukemia

2-Deoxy-2(haloacetamido)-D-glucose and 2-deoxy-2-(haloacetamido)-D-galactose (fluoro, chloro, and bromo) were prepared by de-O-acetylation of the appropriate 1,3,4,6-tetra-O-acetyl-2-deoxy-2-(haloacetamido)-β-D-hexose with triethylamine. The 1,3,4,6-tetra-O-acetyl-2-deoxy-2-(chloroacetamido)- and 1,3,4,6-tetra-O-acetyl-2-deoxy-2-(bromoacetamido)-β-D-hexoses were produced by condensation of a haloacetyl anhydride with 1,3,4,6-tetra-O-acetyl-2-amino-2-deoxy-β-D-hexose hydrochloride in pyridine. The hydrochlorides were converted to free bases for condensation with fluoroacetic acid in the presence of dicyclohexylcarbodiimide to produce 1,3,4,6-tetra-O-acetyl-2-deoxy-2-(fluoroacetamido)-β-D-hexoses. The chloroacetamido and bromoacetamido derivatives were from 3- to 12-fold more toxic on a molar basis to BDF1 mice when administerd as lipophilic tetra-O-acetates than as the free sugars; no significant difference existed between the glucose and galactose forms. The fluoroacetamido analogue of the glucose series was fivefold more toxic than the comparable fluoroacetamido derivative of the galactose series; no difference existed in the toxicities of the free sugars and the tetra-O-acetates with either of the fluoseries; no difference existed in the toxicities of the free sugars and the tetra-O-acetates with either of the fluoroacetamide-containing hexoses. Cytotoxicity against log-phase cultured Friend erythroleukemia cells was greatest with the tetra-O-acetylated bromoacetamido derivatives in both the gluco and galacto series, these agents being three- to fourfold more cytotoxic than tetra-O-acetylated chloroacetamido derivatives and 20-fold more cytotoxic than tetra-O-acetylated fluoroacetamido sugars. The N-chloroacetamido derivative in the glucose series was 50-fold more cytotoxic as the tetra-O-acetate than as the free nonacetylated sugar. These results support the concept that tetra-O-acetylated derivatives of the chloroacetamido and bromoacetamido carbohydrate analogues function as lipophilic alkylating agents and lose biological activity when converted to hydrophilic free hydroxyl forms, whereas the fluoroacetamido derivatives exert their effects as the de-O-acetylated form.