Mitogenic activity and lethal toxicity of lipid A analogs, glucosamine-phosphate carrying aromatic alkyl groups, in mice.
The mitogenicity and lethal toxicity of four synthetic lipid A analogs, glucosamine-4-phosphate with a 7-hydroxy-heptanoyl group (A-166), with a 7-phenyl-heptanoyl group (A-167), or with a 8-(1-phenyl-hexanoyl)-nonanoyl group (A-168), at the C-2 and C-3 positions, and glucosamine-6-phosphate with the same substituents as A-168 at C-2 and C-3 (A-169), were compared. The compound A-166 exhibited no mitogenic activity at various concentrations ranging from 3.13 to 50 micrograms/ml in the splenocytes of BALB/c mice, but A-167 exhibited weak mitogenic activity at concentrations of 12.5 and 25 micrograms/ml. A-168 and A-169, as well as A-103, glucosamine-4-phosphate carrying (R)-3-tetradecanoyl-oxytetradecanoyl groups, have remarkable mitogenic activity at concentrations ranging from 12.5 to 100 micrograms/ml; the activity of A-169 (6-phosphate) was stronger than that of A-168 (4-phosphate). Compound A-167 failed to cause death at doses of 25 and 50 micrograms/mouse in galactosamine-loaded C57BL/6 mice while A-166 and A-169 were toxic to 2 out of 6 mice at 50 micrograms/mouse; no deaths were observed at 25 micrograms/mouse. A-168 showed the highest toxicity of any of the compounds tested at 25 and 50 micrograms/mouse. The lethal effect of A-103 appeared to be somewhere between that of A-168 and A-169. These findings indicate that lipid A analogs, carrying an aromatic alkyl group as well as a hydroxyacyl group, are mitogenic and lethal when given to mice.
Shimizu
T
T
University of Shizuoka, School of Pharmaceutical Sciences, Japan.
Iwamoto
Y
Y
Yanagihara
Y
Y
Itoh
H
H
Nakamoto
S
S
Achiwa
K
K
D000818:Animals; D008050:Lipid A / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008934:Mitogens; D013154:Spleen / Q000166:cytology / Q000187:drug effects*; D013329:Structure-Activity Relationship
D008050:Lipid A; D008934:Mitogens