Interestingly, replacement of the N-acetyl group of GlcNAc with a trifluoroacetyl group depressed [14C]GlcN incorporation by 31% within 5 h, while [3H]leucine incorporation was unaffected. Additionally, treatment of P288 cells with 1 mM GlcNAc resulted in no detectable change in ribonucleotide content, while treatment of cells with N-trifluoroacetyl-GlcN more than doubled the sugar-nucleotide content in the cell. The difference in the biological effects and metabolism of these compounds remains poorly understood, but a difference in cell permeability may be responsible.
Derivatives in which the anomeric position of GlcNAc was modified were also evaluated as potential metabolic inhibitors of glycoconjugate biosynthesis [45,46]. In these fully acetylated compounds, the hydroxyl group at the anomeric position was replaced by a variety of groups including amino, N-chloroacetyl, N-bromoacetyl, N-iodoacetyl, N-trifluoroacetyl, and N-trifluoromethanesulfonyl groups. These GlcNAc derivatives were potent growth inhibitors of either mouse mammary adenocarcinoma TA3 or L1210 leukemia cells with IC50 values in the micromolar range (Table 3). Toxicity of these compounds might simply reflect their alkylating activity. Further modification of GlcNAc to S-glycosyl derivatives revealed that the 1-chlo-roacetylthio, 1-S-diphenylmethyl, and 1-S-trityl, inhibited the growth of TA3 cells at micromolar concentrations (Table 3). In yet another study, a ManN derivative con-
Table 3 Growth Inhibitory Activity of GlcNAc Derivatives Displaying Unnatural Anomeric Substituents Against TA3 Mammary Cells
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