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

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Abstract
Haloacetamido analogs (fluoro, chloro and bromo) of 2-deoxy-2-acetamido-D-mannose and their tetra-O-acetates were prepared from D-mannosamine hydrochloride, with chloroacetic or bromoacetic anhydride or by dicyclohexylcarbodiimide-activated condensation with fluoroacetate followed by acetylation. Comparative specific rotations and 13C and PMR 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 analog of glucose inhibited [3H]thymidine incorporation into mouse L1210 leukemia cells by 50% (IC50) at concentrations between 6 and 9 .mu.M. 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 .mu.M, IC50) than was the corresponding analog in the glucose series (425 .+-. 62 .mu.M; P = 0.005). All of the haloacetamido free sugars, and the tetra-O-acetates of the fluoroacetamido analogs in the glucose, galactose and mannose series, were inactive in the thymidine incorporation assay at 1 mM. In the glucose, galactose and mannose series, were inactive in the thymidine incorporation assay at 1 mM. In the mannose series the tetra-O-acetylated chloroacetamido and bromoacetamido analogs and the bromoacetamido free sugar, could be administered at relatively high in vivo tolerated doses compared to the corresponding analogs in the galactose and glucose series. The 3 mannose analogs produced high proportions of cures of Ehrlich ascites carcinoma-bearing B6D2F1 mice, whereas in the galactose and glucose series only the tetra-O-acetylated bromoacetamido analogs had previously produced in vivo chemotherapeutic activity.