Haloacetamido analogues of 2-amino-2-deoxy-D-mannose. Syntheses and effects on tumor-bearing mice

Haloacetamido analogues (fluoro, chloro, and bromo) of 2-deoxy-2acetamido-D-mannose and their tetra-O-acetates were prepared from D-mannosamine hydrochloride, with either chloroacetic or bromoacetic anhydride or by dicyclohexylcarbodiimide-activated condensation with fluoroacetate followed by acetylation. Comparative specific rotations and 13C and 1H NMR spectra were consistent with a beta configuration for the tetra-O-acetylated derivatives, 1,3,4,6-Tetra-O-acetyl-2-deoxy-2-(bromoacetamido)-beta-D-mannose and the corresponding analogue of glucose inhibited [3H]thymidine incorporation into mouse L1210 leukemia cells by 50% (IC50) at concentrations between 6 and 9 microM. 1,3,4,6-Tetra-O-acetyl-2-deoxy-2-(chloroacetamido)-beta-D-mannose was 3-fold more active in the thymidine-incorporation assay (143 +/- 24 microM, IC50) than was the corresponding analogue in the glucose series (425 +/- 62 microM; p = 0.05). All of the haloacetamido free sugars, as well as the tetra-O-acetates of the fluoroacetamido analogues in the glucose, galactose, and mannose series, were inactive in the thymidine incorporation assay at 1mM. In the mannose series the tetra-O-acetylated chloroacetamido and bromoacetamido analogues, as well as the bromoacetamido free sugar, could be administered at relatively high in vivo tolerated doses compared to the corresponding analogues in the galactose and glucose series. These three mannose analogues produced high proportions of cures of Ehrlich tumor-bearing B6D2F1 mice, whereas in the galactose and glucose series only the tetra-O-acetylated bromoacetamido analogues had previously produced in vivo chemotherapeutic activity.