Biological activities of chemically synthesized N-acylated serine-linked lipid A analog in mice

The mitogenicity, lethal toxicity and antitumor activity against Meth A fibrosarcoma and the induction of tumor necrosis factor (TNF) of chemically synthesized N-acylated serine-linked nonphosphorylated acylglucosamine-derived lipid A analog (A-601, A-602 and A-603) were determined. Compounds A-603 (with (R)-3-tetradecanoyloxytetradecanoyl at the C-2 position) and A-103 (2,3-acyloxyacylglucosamine-4-phosphate) induced significant incorporations of [3H]thymidine into splenocytes of C3H/He mice at concentrations ranging from 6.25 to 100 microM. The mitogenicity of A-601 and A-602 (with tetradecanoyl at the C-2 position) exhibited a lower activity than of A-603. Compounds A-601 and A-603 showed almost the same lethality at doses from 1 to 50 nmol/mouse in C57BL/6 mice loaded with D-galactosamine, whereas A-103 caused the death of two out of six mice at a dose of 25 nmol/mouse. A-601 and A-603 showed weak antitumor activity against Meth A fibrosarcoma in BALB/c mice, but there was no enhancement of antitumor activity by a combination of A-603 with muramyl dipeptide. Peritoneal macrophages, stimulated with A-601, A-602 or A-603, caused production of TNF which induces L929 cell lysis in vitro. But the activity of A-603 among the compounds on TNF-production was the highest. These findings indicate that the linkage of nonphosphorylated acylglucosamine and N-acylated serine affects the expression of the biological activity.