Comparison of the biological activity of synthetic N-acylated asparagine or serine linked monosaccharide lipid A analogs.

Abstract

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.

• Authors: T Shimizu, Y Iwamoto, Y Yanagihara, K Ryoyama, Y Suhara, K Ikeda, K Achiwa
• Journal: Immunobiology (Immunobiology) Vol. 196 Issue 4 Pg. 321-31 ( 1996) ISSN: 0171-2985 [Print] Netherlands
• PMID: 9061373 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Lipid A
• Mitogens
• Monosaccharides
• Tumor Necrosis Factor-alpha
• Nitric Oxide
• Serine
• Asparagine

Topics

• Acylation
• Animals
• Antineoplastic Agents (pharmacology)
• Asparagine (chemical synthesis, metabolism)
• Fibrosarcoma (drug therapy)
• Lipid A (analogs & derivatives, chemical synthesis, metabolism, toxicity)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C3H
• Mice, Inbred C57BL
• Mitogens (metabolism, toxicity)
• Monosaccharides (chemical synthesis, metabolism)
• Nitric Oxide (biosynthesis)
• Sarcoma, Experimental (drug therapy)
• Serine (metabolism)
• Tumor Necrosis Factor-alpha (biosynthesis)