Biological activity of chemically synthesized core sugar linked lipid A analog, heptose-(alpha 1----5)-2-keto-3-deoxyoctonic acid-(alpha 2----6)-2,3-diacyloxyacylglucosamine-4-phosphate.
The mitogenicity, lethal toxicity and antitumor activity against Meth A fibrosarcoma and the induction of tumor necrosis factor (TNF) of chemically synthesized compounds designated as A-103, 2,3-diacyloxyacylglucosamine-4-phosphate (GlcN-4-P), and A-503), heptose-(alpha 1----5)-2-keto-3-deoxyoctonic acid (KDO)-linked GlcN-4-P (A-103), were determined. Compound A-103 induced significant incorporation of [3H]thymidine of C57BL/6 mice at 25-100 micrograms/ml, and A-503 showed the highest incorporation of [3H]thymidine at 100 micrograms/ml. The mitogenicity of A-503 exhibited a lower activity than of A-103. Compound A-503 showed no lethality at high doses of 25 and 50 micrograms/mouse in C57BL/6 mice loaded with D-galactosamine, whereas A-103 caused the death of one of three mice at a dose of 50 micrograms/mouse. Although, the two compounds with or without muramyl dipeptide showed weak antitumor activity against Meth A fibrosarcoma in BALB/c mice, but there were no remarkable differences between the compounds on antitumor activity. Peritoneal macrophages, stimulated with A-103 or A-503 caused no production of TNF which induces L929 cell lysis in vitro. These findings indicate that the addition of heptose and KDO to GlcN-4-P seems not to affect mitogenic activity, lethal toxicity, antitumor activity and TNF-production of the GlcN-4-P compound (A-103).
Shimizu
T
T
Department of Microbiology, University of Shizuoka, School of Pharmaceutical Sciences, Japan.
Ohtsuka
Y
Y
Yanagihara
Y
Y
Akamatsu
S
S
Ikeda
K
K
Achiwa
K
K
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008934:Mitogens / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000970:Antineoplastic Agents; D008050:Lipid A; D008070:Lipopolysaccharides; D008934:Mitogens; D014409:Tumor Necrosis Factor-alpha; C075552:A 503