Halogenated L-fucose and D-galactose analogs: synthesis and metabolic effects

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Abstract
Several new analogs of L-fucose modified in the 2 position and the 5-methyl group were synthesized as potential plasma-membrane glycoconjugate inhibitors or modifiers, and their biological effects were studied. 2-Chloro-, 2-bromo and 2-iodo-2-deoxy-L-fucose (9a, 9b and 13, respectively) were prepared by addition of the appropriate halogen to 3,4-di-O-acetyl-L-fucal, followed by hydrolysis of the anomeric halogen and the acetyl groups. A series of 4 halogenated 5-methyl analogs of L-fucose (4, X = F, Cl, Br and I) were obtained starting from 1,2:3,4-di-O-isopropylidene-L-galactose. The synthesis of this latter compound was improved. A corresponding series of 6-deoxy-6-halo-D-galactose analogs, which are enantiomers of the 5-(halomethyl)-L-fucose analogs, also was synthesized. Analogs 4b, 4c and 9b at 1 .times. 10-3 M specifically inhibited the incorporation of L-[3H]fucose into macromolecular components of SW613 human mammary tumor cells. Analogue 13 inhibited the growth of L1210 murine leukemic cells with an IC50 of 6 .times. 10-5 M in culture. 6-Deoxy-6-fluoro-D-galactose and its enantiomer 4a were effective inhibitors of D-[3H]galactose and L-[3H]fucose incorporation, respectively, into macromolecular components of human mammary tumor cells. The effectiveness of inhibition was reduced with an increase in size of the halogen atom. Analog 4a and its enantiomer were tritiated at C-1 and both were activated to nucleotide sugar, which was followed by incorporation into the macromolecular fraction of SW613 human mammary tumor cells in vitro. [Neoplastic changes in plasma membrane structure and function are discussed in relation to chemotherapy.].