title: Low endotoxic activities of synthetic Salmonella-type lipid A with an additional acyloxyacyl group on the 2-amino group of beta (1-6) glucosamine disaccharide 1,4'-bisphosphate.
abstract: A synthetic lipid A (Salmonella type, compound 516), beta (1-6)-linked D-glucosamine disaccharide 1,4'-bisphosphate, with three acyloxyacyl groups and one hydroxyacyl group, i.e., (R)-3-hexadecanoyloxytetradecanoyl, (R)-3-hydroxytetradecanoyl, (R)-3-dodecanoyloxytetradecanoyl, and (R)-3-tetradecanoyloxytetradecanoyl groups at the 2-amino, 3-hydroxyl, 2'-amino, and 3'-hydroxyl groups, respectively, was less biologically active than the synthetic Escherichia coli-type lipid A (compound 506), which has only two acyloxyacyl groups at the 2' and 3' positions and is substituted with a (R)-3-hydroxytetradecanoyl group at the 2-amino group. Compound 516 exhibited considerably weaker pyrogenic and leukopenic activity than compound 506, and it scarcely prepared rabbit skin for the Shwartzman reaction and lacked lethal toxicity on chicken embryos, although its lethal toxicity in galactosamine-loaded mice was as strong as that of compound 506. Compound 516 was also less active than compound 506 or natural E. coli lipid A (from Restrain F515) in other biological test systems, such as the Limulus test, stimulation of macrophages and lymphocytes, and interferon-inducing activity but not for interleukin-1 induction or complement activation. This observation suggests that there is an optimal number of acyloxyacyl groups on the glucosamine backbone for producing the biological activities of lipid A, especially the endotoxic activities. The 4'-monophosphate analog (compound 514) of compound 516 in general had significantly weaker activity than compound 516 in the above assays, most probably because of its greater hydrophobicity and consequently lower solubility in assay systems. Bacterial R595 lipid A derived from S. minnesota Re-mutant, which is a mixture of compounds 516 and 506, their 4'-monophosphate analogs and other compounds, exerted intermediate degrees of activity between compounds 506 and 516 in the various test systems employed.
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D002642:Chick Embryo; D003167:Complement Activation; D003603:Cytotoxins / Q000096:biosynthesis; D015232:Dinoprostone; D004731:Endotoxins / Q000633:toxicity*; D005944:Glucosamine / Q000378:metabolism; D007370:Interferon Type I / Q000096:biosynthesis; D007375:Interleukin-1 / Q000096:biosynthesis; D007958:Leukocyte Count / Q000187:drug effects; D008033:Limulus Test; D008050:Lipid A / Q000138:chemical synthesis / Q000633:toxicity*; D008213:Lymphocyte Activation / Q000187:drug effects; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D011458:Prostaglandins E / Q000096:biosynthesis; D011749:Pyrogens; D012475:Salmonella / Q000472:pathogenicity*; D012790:Shwartzman Phenomenon; D013329:Structure-Activity Relationship; D013481:Superoxides / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D003603:Cytotoxins; D004731:Endotoxins; D007370:Interferon Type I; D007375:Interleukin-1; D008050:Lipid A; D011458:Prostaglandins E; D011749:Pyrogens; D013481:Superoxides; D015232:Dinoprostone; D005944:Glucosamine