Synthesis of lyposaccharide corresponding to fundamental structure of Salmonella-type lipid A

Inage, Masaru; Chaki, Haruyuki; Kusumoto, Shoichi; Shiba, Tetsuo

doi:10.1016/0040-4039(80)80208-5

Cited by 32 publications

(4 citation statements)

References 6 publications

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“…Materials. Salmonella minnesota S and Re lipopolysaccharides, free lipid A from S. minnesota Re (6, 7), the synthetic lipid A analogs (10)(11)(12), and the succinylated derivatives are described in an accompanying paper (23). The structures and designations of the synthetic preparations are shown in Fig.…”

Section: Methodsmentioning

confidence: 99%

Mitogenic activities of synthetic lipid A analogs and suppression of mitogenicity of lipid A

Tanamoto¹,

Galanos²,

Lüderitz³

et al. 1984

Infect Immun

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The effect of synthetic lipid A analogs on murine spleen cells was studied. The preparations represented D-glucosamine and D-glucosaminyl-beta 1,6-D-glucosamine disaccharide derivatives substituted in different combinations by ester- and amide-bound fatty acids and by phosphate groups. Significant mitogenic activity was demonstrated with a number of synthetic disaccharide preparations; however, their potency was lower than that of lipid A. The synthetic preparations were not mitogenic for spleen cells from C3H/HeJ mice. Furthermore, the mitogenicity of the synthetic preparations was abolished after binding with polymyxin B. The results indicate that for expression of mitogenicity, a phosphate group at position 1 of the reducing glucosamine and amide-bound acyloxyacyl residues are important factors. Some of the synthetic preparations containing the diglucosamine backbone and expressing relatively low mitogenicity suppressed B-cell mitogenicity of lipid A. Although these preparations were lytic for erythrocytes, they did not affect the viability of the splenic lymphocytes. Suppression was seen when the synthetic preparations were added simultaneously with or after the lipid A mitogen, but optimal suppression was expressed when the preparations were added to the system 3 h before lipid A. Washing of the cells before the addition of lipid A did not affect the results. The suppression was not due to the induction of suppressor cells by the synthetic preparations. The disaccharide preparations did not inhibit T-cell mitogenicity of concanavalin A. In contrast to the disaccharide preparations, the monosaccharide preparations suppressed mitogenicity of both lipid A and concanavalin A, probably because of their direct toxicity for lymphocytes.

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Section: Methodsmentioning

confidence: 99%

Mitogenic activities of synthetic lipid A analogs and suppression of mitogenicity of lipid A

Tanamoto¹,

Galanos²,

Lüderitz³

et al. 1984

Infect Immun

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“…1) were prepared from benzyl-2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-aor -,-D-glucopyranoside as follows. After removal of the N-acetyl group with Meerwein reagent (12), the free amino group was acylated with tetradecanoyl chloride or with (R)-or (S)-3-hydroxytetradecanoic acid-dicyclohexylcarbodiimide, respectively (33). Each N-acylated compound thus obtained was then treated with concentrated aqueous ammonia in methanol and hydrogenolyzed to give compound 308, 309, or 310.…”

Section: Methodsmentioning

confidence: 99%

Immunobiological activities of synthetic lipid A analogs and related compounds as compared with those of bacterial lipopolysaccharide, re-glycolipid, lipid A, and muramyl dipeptide

et al. 1983

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Thirteen acylated and phosphorylated derivatives of 0-1,6-linked glucosamine disaccharide (lipid A analogs), which were synthesized after the structural model of Salmonella-type lipid A, and seven similar derivatives of glucosamine monosaccharide (lipid A-related compounds) were studied for their immunobiological activities. These included mitogenicity and polyclonal B cell activation enhancement of migration of monocytes and polymorphonuclear leukocytes derived from human peripheral blood, stimulation of guinea pig peritoneal macrophages, activation of human complement, and stimulation of serum antibody production and induction of delayed-type hypersensitivity against ovalbumin in guinea pigs. Comparisons were made with lipid A, Re-glycolipid, lipopolysaccharide of natural sources, and a well-known synthetic adjuvant, N-acetylmuramyl-L-alanyl-Disoglutamine. Some of the lipid A analogs were found to manifest the mitogenic, polyclonal B cell-activating macrophage-stimulating, complement-activating, and immunostimulating activities, although the observed activities were generally far less than those of natural products in intensity and efficiency. Other immunobiological effects exhibited by most of the synthetic lipid A analogs were the enhancement of migration of monocytes and polymorphonuclear leukocytes. It is premature to draw definite conclusions on structure-activity relationships, since a few compounds which were active in some assay systems were scarcely active in other assays. However, an indisputable fact was that P-1,6-glucosamine disaccharide la,4'-diphosphate, which carries two amide-bound (R)-3-hydroxytetradecanoyl and three ester-bound tetradecanoyl residues, and thus has the structure most closely resembling natural lipid A among test compounds in this study, was definitely active in all of the present assay systems. However, its potency was generally much less than natural products. Some of glucosamine monosaccharide derivatives, especially N-(R)-3-[(R)-3-hydroxytetradecanoyloxy]tetradecanoyI glucosamine, also exerted all of the in vitro activities described above. This fact suggests that a glucosamine disaccharide structure may not necessarily be a prerequisite as far as the in vitro immunobiological activities tested are concerned.

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“…Stimulants of prostaglandin release. Lipopolysaccharide (LPS) from Salmonella minnesota R595 (7) and the synthetic lipid A analogs (12)(13)(14) have been described previously (30). The chemical structures of the synthetic preparations used in this study are shown in Fig.…”

Section: Methodsmentioning

confidence: 99%

Endotoxic induction of prostaglandin release from macrophages by nontoxic lipid A analogs synthesized chemically

et al. 1990

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The ability of synthetic lipid A analogs to induce prostaglandin synthesis in macrophages was compared with that of native lipopolysaccharide. The synthetic preparations comprised monomeric or dimeric derivatives of D-glucosamine with different patterns of substitution by phosphate and tetradecanoic, (R)-3-hydroxytetradecanoic, and (R)-3-tetradecanoyloxytetradecanoic acid. All of these preparations are structurally distinct from native lipid A (principally regarding the position of fatty acid substitution) and hence have been previously shown to be endotoxically inactive in many biological tests. It was found that many of these synthetic samples exhibit strong activity in inducing prostaglandin E2 and prostaglandin F2 alpha, with some of them having activity comparable to that of lipopolysaccharide. Experiments with macrophages of C3H/HeJ mice enabled us to differentiate between endotoxin-specific (in the case of dimeric preparations) and endotoxin-nonspecific (for monomeric preparations) mechanisms for the induction of prostaglandins. These results indicate that there is a difference in the mechanism of induction of prostaglandin synthesis between monomeric lipid A's and dimeric or native lipid A structures.

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Synthesis of lyposaccharide corresponding to fundamental structure of Salmonella-type lipid A

Cited by 32 publications

References 6 publications

Mitogenic activities of synthetic lipid A analogs and suppression of mitogenicity of lipid A

Mitogenic activities of synthetic lipid A analogs and suppression of mitogenicity of lipid A

Immunobiological activities of synthetic lipid A analogs and related compounds as compared with those of bacterial lipopolysaccharide, re-glycolipid, lipid A, and muramyl dipeptide

Endotoxic induction of prostaglandin release from macrophages by nontoxic lipid A analogs synthesized chemically

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