Biological activities of chemically synthesized N-acylated serine-linked lipid A analog in mice.
The mitogenicity, lethal toxicity and antitumor activity against Meth A fibrosarcoma and the induction of tumor necrosis factor (TNF) of chemically synthesized N-acylated serine-linked nonphosphorylated acylglucosamine-derived lipid A analog (A-601, A-602 and A-603) were determined. Compounds A-603 (with (R)-3-tetradecanoyloxytetradecanoyl at the C-2 position) and A-103 (2,3-acyloxyacylglucosamine-4-phosphate) induced significant incorporations of [3H]thymidine into splenocytes of C3H/He mice at concentrations ranging from 6.25 to 100 microM. The mitogenicity of A-601 and A-602 (with tetradecanoyl at the C-2 position) exhibited a lower activity than of A-603. Compounds A-601 and A-603 showed almost the same lethality at doses from 1 to 50 nmol/mouse in C57BL/6 mice loaded with D-galactosamine, whereas A-103 caused the death of two out of six mice at a dose of 25 nmol/mouse. A-601 and A-603 showed weak antitumor activity against Meth A fibrosarcoma in BALB/c mice, but there was no enhancement of antitumor activity by a combination of A-603 with muramyl dipeptide. Peritoneal macrophages, stimulated with A-601, A-602 or A-603, caused production of TNF which induces L929 cell lysis in vitro. But the activity of A-603 among the compounds on TNF-production was the highest. These findings indicate that the linkage of nonphosphorylated acylglucosamine and N-acylated serine affects the expression of the biological activity.
Shimizu
T
T
Department of Microbiology, University of Shizuoka, School of Pharmaceutical Sciences, Japan.
Sugiyama
K
K
Iwamoto
Y
Y
Yanagihara
Y
Y
Asahara
T
T
Ikeda
K
K
Achiwa
K
K
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D005688:Galactosamine / Q000494:pharmacology; D007928:Lethal Dose 50; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D008070:Lipopolysaccharides / Q000302:isolation & purification / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D012486:Salmonella typhimurium / Q000737:chemistry; D012513:Sarcoma, Experimental / Q000188:drug therapy; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
C090843:A 602; C090845:A 603; D000970:Antineoplastic Agents; D008050:Lipid A; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C090841:A 601; D005688:Galactosamine