The mitogenicity, lethal toxicity, induction of
tumor necrosis factor (TNF), production of
nitric oxide (NO) and antitumor activity against Meth A
fibrosarcoma by chemically synthesized N-acylated
asparagine-linked (A-701, A-702 and A-703) or N-acylated
serine-linked (A-607) nonphosphorylated acylglucosamine and 4-0-phosphorylated acylglucosamine (A-103) derived
lipid A analogs were determined. compound A-607 (with tetradecanoyl and (R)-3-tetradecanoyloxytetradecanoyl at the C-2 and C-3 positions) induced a significant incorporation of 3H-thymidine into splenocytes of C3H/He mice at concentrations ranging from 3.13 to 50 microM, but the mitogenic activity of A-701 (2-N-acetylglucosamine), A-702 (tetradecanoyl at the C-2), and A-703 (with (R)-tetradecanoyloxytetradecanoyl and tetradecanoyl at the C-2 and C-3) was very weak. The lethality of A-703 and
A-103 (with (R)-3-tetradecanoyloxytetradecanoyl at the C-2 and C-3) was weaker than that of A-607 at doses of 300 and 750 nmol/kg in C57BL/6 mice loaded with D-
galactosamine. Peritoneal macrophages, stimulated with A-701-A-703, caused production of TNF which induce L929 cell lysis in vitro, and A-703 showed a high production of TNF. The compounds, except for A-607, exhibited little NO production by macrophages, but did induce the NO production in the presence of
interferon gamma. Induction of TNF and NO inducible activity by A-703 was lower than that of A-607. A-703, A-607 and
A-103 showed antitumor activity against Meth A
fibrosarcoma in BALB/c mice. When A-703 or
A-103 with
muramyl dipeptide was administered, A-703 failed to show combined effects, but
A-103 did. We concluded from these findings that the
biological potency of
asparagine compounds appears to be placed between
serine- and amino-free compounds.