The mitogenicity, lethal toxicity, production of
nitric oxide (NO), induction of
tumor necrosis factor (TNF) and antitumor activity against Meth A
fibrosarcoma by chemically synthesized N-acylated
serine-linked non-phosphorylated (A-606 and A607) and phosphorylated (A-608) acylglucosamine-derived
lipid A analog were determined. Compounds A-606, A-608 and
A-103 [with (R)-3-tetradecanoyloxytetradecanoyl at the C-2 and C-3 positions] induced significant incorporation of [3H]
thymidine into splenocytes of C3H/He mice at concentrations ranging from 3.13 to 50 microM. However, A-607 [with (R)-3-tetradecanoyloxytetradecanoyl and with tetradecanoyl at the C-2 and C-3 positions] showed most significant incorporation of [3H]
thymidine. The compounds A-606, A-608 and
A-103 did not exhibit the lethality at doses of 30 and 300 nmol/kg in C57BL/6 mice loaded with D-
galactosamine, whereas A-607 caused the death of two out of six mice at a dose of 300 nmol/kg. These compounds, except A-607, exhibited little NO production by macrophages, but did cause NO production in the presence of
interferon-gamma (IFN-gamma). Peritoneal macrophages, stimulated with A-606-A-608, caused production of TNF which induce L929 cell lysis in vitro, and A-608 showed high production of TNF. NO-inducible activity and induction of TNF by compound
A-103 seemed to be lower than that of
serine-linked derivatives. A-607, A-608 and
A-103 showed antitumor activity against Meth A
fibrosarcoma in BALB/c mice, and furthermore, the enhancement of antitumor activity by a combination of A-608 with
muramyl dipeptide (MDP) was observed.(ABSTRACT TRUNCATED AT 250 WORDS)