Halogenated Monosaccharides

Halogenated compounds have been widely used to study biological processes [48]. The halogens (F, Cl, Br, and I) are readily installed on synthetic analogs and might mimic a polar hydroxyl group. Among the halogens, fluorine has attracted the most attention. A comparison of bond lengths, van der Waals radii, and electronegativities indicates that the C—F bond quite closely resembles the C—OH bond [49]. The similar properties of the fluorine atom and hydroxyl group suggest that substitution might be tolerated by biosynthetic enzymes. The introduction of a fluorohexose or hexosamine analog into a biosynthetic pathway might lead to metabolic incorporation or metabolic disruption. An advantage to the use of fluorosugar analogs is the availability of additional analytical techniques, such as 19F NMR spectroscopy and radiolabeled 18F tracers, that facilitate characterization of downstream metabolic products [50-53].

Independent studies by Korytnyk and coworkers and May and Sartorelli have probed the effects of halogenated fucose (Fuc) and galactose (Gal) analogs on gly-coconjugate biosynthesis [54-56]. Synthetic analogs bearing fluoro, chloro, bromo, or iodo groups at the 2- or 5-positions of Fuc, and the 6-position of Gal were shown to have inhibitory effects on the incorporation of the corresponding natural sugars, [3H]Fuc or [3H]Gal, into glycoproteins (Tables 4 and 5). The growth of murine L1210 leukemia cells was inhibited by 2-iodo-Fuc with an IC50 value of 0.06 mM (Table 4). Similarly, when mice with L1210 ascites tumors were injected with either 6-fluoro-Gal (Table 5) or 2-bromo-Fuc (Table 4), their life span was prolonged by 32 and 25%, respectively. The 6-methanesulfonyl (Ms) analog of Gal had similar tox-icity against L1210 leukemia cells. Other halogenated derivatives of Fuc such as 2-bromo-Fuc, 6-chloro-Fuc, and 6-bromo-Fuc were much less toxic, with very little activity at concentrations above 1 mM (Table 4). The 6-halogenated analogs of Gal had inhibitory effects similar to those of their enantiomers, the corresponding 6-halogenated-Fuc analogs (Table 5). Some halogenated analogs displayed cell-type-specific effects: 6-fluoro-Fuc did not inhibit the growth of L1210 leukemia cells at 1 mM, although it did reduce the incorporation of [3H]Fuc by 91% in human mammary tumor cells. Other compounds, such as 6-fluoro-Gal, although appearing non-toxic at 1 mM, had significant inhibitory effects toward the incorporation of [3H]Gal in P2888 murine lymphoma cells [55]. Westwood and coworkers have investigated the antitumor activity of fluorohexoses in vivo. From a panel of 6-halogenated Gal and Glc analogs, only 6-fluoro-Glc exhibited significant antitumor activity, blocking the growth of R-1 lymphoma up to 90% in mice [57].

Fluorohexosamine analogs that have been used in metabolic studies include 6-fluoro-ManNAc, 6-fluoro-ManN, methyl 3-fluoro-ManNAc, 3-fluoro-GlcNAc, 4-fluoro-GlcNAc, and 4-fluoro-GalNAc [58-60]. Many of these compounds were evaluated in both acetylated and nonacetylated forms. Among several 6-fluoro analogs

Table 4 Toxicity or Growth Inhibitory Activity of Fuc Derivatives Against L1210 Leukemia Cells

Fuc
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