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-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.
Shimizu
T
T
Department of Microbiology, University of Shizuoka, School of Pharmaceutical Sciences, Japan.
Iwamoto
Y
Y
Yanagihara
Y
Y
Ryoyama
K
K
Suhara
Y
Y
Ikeda
K
K
Achiwa
K
K
D000215:Acylation; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001216:Asparagine / Q000138:chemical synthesis / Q000378:metabolism*; D005354:Fibrosarcoma / Q000188:drug therapy; D008050:Lipid A / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism* / Q000633:toxicity; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008934:Mitogens / Q000378:metabolism / Q000633:toxicity; D009005:Monosaccharides / Q000138:chemical synthesis / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis; D012513:Sarcoma, Experimental / Q000188:drug therapy; D012694:Serine / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000970:Antineoplastic Agents; D008050:Lipid A; D008934:Mitogens; D009005:Monosaccharides; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D012694:Serine; D001216:Asparagine