BIOLOGICAL-ACTIVITIES AND ANTITUMOR EFFECTS OF SYNTHETIC LIPID A ANALOG LINKED N-ACYLATED SERINE

The mitogenicity, lethal toxicity, production of nitric oxide (NO), in duction 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) acylgl ucosamine-derived lipid A analog were determined. Compounds A-606, A-6 08 and A-103 [with (R)-3-tetradecanoyloxytetradecanoyl at the C-2 and C-3 positions] induced significant incorporation of [H-3]thymidine int o splenocytes of C3H/He mice at concentrations ranging from 3.13 to 50 mu M. However, A-607 [with (R)-3-tetradecanoyloxytetradecanoyl and wi th tetradecanoyl at the C-2 and C-3 positions] showed most significant incorporation of [H-3]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 N O production in the presence of interferon-gamma (IFN-gamma). Peritone al macrophages, stimulated with A-606-A-608, caused production of TNF which induce L929 cell lysis in vitro, and A-608 showed high productio n 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-6 08 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. The findings indicated that the presence of phosphoryl group in the N-acy lated serine-linked acylglucosamine derivative is important for the ex pression of the antitumor activity and combined effect with MDP.