COMPARISON OF THE BIOLOGICAL-ACTIVITY OF SYNTHETIC N-ACYLATED ASPARAGINE OR SERINE LINKED MONOSACCHARIDE LIPID A ANALOGS

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-li nked (A-701, A-702 and A-703) or N-acylated serine-linked (A-607) nonp hosphorylated acylglucosamine and il 4-0-phosphorylated acylglucosamin e (A-103) derived lipid A analogs were determined. Compound A-607 (wit h tetradecanoyl and (R)-3-tetradecanoyloxytetradecanoyl at the C-2 and C-3 positions) induced a significant incorporation of H-3-thymidine i nto splenocytes of C3H/He mice at concentrations ranging from 3.13 to 50 mu M, but the mitogenic activity of A-701 (2-N-acetylglucosamine), A-702 (tetradecanoyl at the C-2), and A-703 (with (R)-tetradecanoyloxy tetradecanoyl and tetradecanoyl at the C-2 and C-3) was very weak. The lethality of A-703 and A-103 (with (R)-3-tetradecanoyloxytetradecanoy l at the C-2 and C-3) was weaker than that of A-607 at doses of 300 an d 750 nmol/kg in C57BL/b mice loaded with D-galactosamine. Peritoneal macrophages, stimulated with A-701-A-703, caused production of TNF whi ch induce L929 cell lysis in vitro, and A-703 showed a high production of TNF The compounds, except for A-607, exhibited little NO productio n 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-1 03 with muramyl dipeptide was administered, A-703 failed to show combi ned effects, but A-103 did. We concluded from these findings that the biological potency of asparagine compounds appears to be placed betwee n serine- and amino-free compounds.