Antitumor activity, mitogenicity, and lethal toxicity of chemically synthesized monosaccharide analogs of lipid A

Antitumor activity of three derivatives of chemically synthesized diacyloxyacylglucosamine-4-phosphate (acyl-GlcN-4P) linked 3-deoxy-D-manno-2-octulosonic acid (KDO) and 12 derivatives of acyl-GlcN-4P or acyloxyacylglucosamine-6-phosphate (acyl-GlcN-6P) with chiral acyloxyacyl groups at the C-2 and C-3 positions was examined. Ehrlich carcinoma cells (1 x 10(4] were inoculated i.p. into ddY mice on day 0, and these compounds (100 micrograms/d/mouse) were administered i.p. on days -5, -2, +1, +3, and +5. Although the antitumor activity of the acyl-GlcN-4P linked KDO was weaker than that of the natural lipopolysaccharide, groups of mice administered A-301 with di-3-hexadecanoyloxytetradecanoyl [(R)C14-O-C16] at C-2, -3, and A-303 with di-3-tetradecanoyloxytetradecanoyl [(R)C14-O-C14] showed longer mean survival times than the control group. However, KDO-attachment appeared not to enhance the antitumor activity of acyl-GlcN-4P. The group of mice administered acyl-GlcN-4P (A-145) or acyl-GlcN-6P (A-144 and A-146), which have an acyloxyacyl group at C-2, -3, showed prolonged survival times when compared to the control group, but the differences were not significant. On the other hand, when compound A-107 with [(S)C14-O-C14] at the C-2 position and 6-phosphate was administered to 5 mice, 3 mice survived for 25 d. Furthermore, mitogenicity for splenocytes of C57BL/6 mice and lethal toxicity in C57BL/6 mice sensitized with D-galactosamine were observed with the acyl-GlcN-4P or -6P derivatives with (R) or (S) isomers of fatty acid.(ABSTRACT TRUNCATED AT 250 WORDS)