title: Synthesis of lipid A and its analogues for investigation of the structural basis for their bioactivity.
abstract: As a step to elucidate the structural requirements for the endotoxic and antagonistic activity of lipid A derivatives, we have focused, in the present study, on the effects of the acyl moieties and acidic groups at the 1- and 4'- positions. We synthesized a new analogue corresponding to Rubrivivax gelatinosus lipid A, which has a characteristic symmetrical distribution of acyl groups on the two glucosamine residues with shorter acyl groups (decanoyl groups [C(10)] and lauryl groups [C(12)]) than Escherichia coli lipid A. Carboxymethyl analogues in which one of the phosphates was replaced with a carboxymethyl group were also synthesized with different distribution of acyl groups. Biological tests revealed that the distribution of acyl groups strongly affected the bioactivity. The synthetic Ru. gelatinosus type lipid A showed potent antagonistic activity against LPS, whereas its 1-O-carboxymethyl analogue showed weak endotoxic activity. These results demonstrated that when the lipid A has shorter (C(10), C(12)) hexa-acyl groups, the bioactivity of lipid A is easily affected with small structural difference, such as the difference of acidic group or the distribution of acyl groups, and the bioactivity changes from endotoxic to agonistic or vice versa at this structural boundary for the bioactivity. We also designed, based on molecular mechanics calculations, and synthesized lipid A analogues possessing acidic amino acid residues in place of the non-reducing end phosphorylated glucosamine. Definite switching of the endotoxic or antagonistic activity was also observed depending on the difference of the acidic groups (phosphoric acid or carboxylic acid) in the lipid A analogues.
authors.affiliation: Department of Chemistry, Graduate School of Science, Osaka University, Toyonaka, Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Fujimoto
authors.forename: Yo
authors.initials: Y
authors.lastname: Adachi
authors.forename: Masao
authors.initials: M
authors.lastname: Akamatsu
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Fukase
authors.forename: Mikayo
authors.initials: M
authors.lastname: Kataoka
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Suda
authors.forename: Koichi
authors.initials: K
authors.lastname: Fukase
authors.forename: Shoichi
authors.initials: S
authors.lastname: Kusumoto
mesh_terms: D004731:Endotoxins / Q000037:antagonists & inhibitors; D015850:Interleukin-6 / Q000096:biosynthesis; D008033:Limulus Test; D008050:Lipid A / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D008968:Molecular Conformation; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D004731:Endotoxins; D015850:Interleukin-6; D008050:Lipid A; D014409:Tumor Necrosis Factor-alpha