EXPRESSION OF ENDOTOXIC ACTIVITIES BY SYNTHETIC MONOSACCHARIDE LIPID-A ANALOGS WITH ALKYL-BRANCHED ACYL SUBSTITUENTS

Synthetic monosaccharide lipid A analogs with alkyl-branched acyl subs tituents instead of the usual ester-branched acyl substituents were in vestigated for their biological activities, The activities were compar ed with those of a representative synthetic monosaccharide lipid A ana log with an ester branch (GLA-60) and synthetic complete lipid A (506) to estimate the role of the attaching mode of the branched side chain s for expression of endotoxic activities, Among the analogs with alkyl branches, GLA-146 and GLA-147, which have C-12 and C-14 alkyl side ch ains, respectively, showed strong endotoxic activities, These analogs exhibited comparable or stronger activities than those of GLA-60 in mu rine macrophage activation activities to induce mediators such as tumo r necrosis factors, interleukin 6, and nitric oxide and in mitogenic a ctivity towards murine spleen cells; however, these activities were we aker than the respective activities of 506, With respect to lethal tox icity to galaetosamine-sensitized mice, the analogs showed stronger ac tivity than that of GLA-60 and activity closer to that of 506, With re spect to adjuvant activity, no significant activity was observed in th e analogs, while the activities of GLA-60 and 506 were strong, When li popolysaccharide-resistant C3H/HeJ mice were used, the activities desc ribed above were not observed either for the analogs under investigati on nor for GLA-60 and 506, These findings indicate that the ester type of branch in lipid A and its analogs does not play an indispensable r ole in the expression of various endotoxic activities, However, it may play some role in the expression of adjuvant activity and in lowering the level of toxicity.