Synthesis of 2-deoxy-4-O-phosphono-3-O-tetradecanoyl-2-[(3R- and (3S)-3-tetradecanoyloxytetradecanamido]-d-glucose: a diastereoisomeric pair of 4-O-phosphono-d-glucosamine derivatives (GLA-27) related to bacterial lipid A

Kiso, Makoto; Tanaka, Shinji; Tanahashi, Masanori; Fujishima, Yushun; Ogawa, Yasuhiro; Hasegawa, Akira

doi:10.1016/s0008-6215(00)90390-2

Cited by 32 publications

(9 citation statements)

References 35 publications

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“…Chemistry. The target MLA derivatives 3a − f were prepared in a highly convergent manner (Schemes and ) from the known benzyl and 2-(trimethylsilyl)ethyl (TMSEt, SE) β-glycosides 4 and 8 , respectively, and ( R )-3- n -alkanoyloxytetradecanoic acids 5a − f 15 (Chart ). Our strategy, based on our recently reported total synthesis of the major constituents (e.g., compound 2 ) of S. minnesota MPL, utilizes the N -2,2,2-trichloroethoxycarbonyl (Troc) method 17,18 and silver ion catalysis 18 to assemble the key β-(1→6) disaccharide intermediates 13a − f in a stereospecific manner from glycosyl chlorides 12a − f and diols 7a − f .…”

Section: Resultsmentioning

confidence: 99%

3-O-Desacyl Monophosphoryl Lipid A Derivatives: Synthesis and Immunostimulant Activities

Johnson¹,

Keegan²,

Sowell³

et al. 1999

J. Med. Chem.

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The synthesis of a series of novel analogues of lipid A, the active principle of lipopolysaccharide, is reported. In these compounds, the 1-O-phosphono and (R)-3-hydroxytetradecanoyl moieties of native Salmonella minnesota R595 lipid A have been replaced with hydrogen and the length of the normal fatty acyl residues has been systematically varied. Normal fatty acid chain length in the 3-O-desacyl monophosphoryl lipid A (MLA) series is shown to be a critical determinant of iNOS gene expression in activated mouse macrophages and the induction of proinflammatory cytokines in human peripheral monocytes. Examination of pyrogenicity in rabbits and lethal toxicity in D-galactosamine-treated mice shows that toxic effects in the MLA series can be ameliorated by modifying fatty acid chain length. When used as an adjuvant for tetanus toxoid vaccines, certain MLA derivatives enhance the production of tetanus toxoid-specific antibodies in mice.

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Section: Resultsmentioning

confidence: 99%

3-O-Desacyl Monophosphoryl Lipid A Derivatives: Synthesis and Immunostimulant Activities

Johnson¹,

Keegan²,

Sowell³

et al. 1999

J. Med. Chem.

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“…The elucidation of the correct structure of lipid A (8,26) and the subsequent success in the total synthesis of biologically active lipid A and analogs (9)(10)(11)(12)27) have rekindled interest in the possibility of separating the immunostimulatory and toxic moieties of endotoxin. Efforts to identify beneficial immunostimulatory lipid A derivatives have concentrated on synthetic analogs representing both the nonreducing (10)(11)(12) and reducing sugar moieties, such as lipids X and Y (15,27). Synthetic lipid A subunits of the nonreducing sugar moiety such as GLA-27 and GLA-60 were reported to activate B cells and macrophages and to induce release of mediators including gamma interferon and tumor necrosis factor (TNF) at nontoxic doses (for a review, see reference 5).…”

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confidence: 99%

SDZ MRL 953, a novel immunostimulatory monosaccharidic lipid A analog with an improved therapeutic window in experimental sepsis

Lam

Schütze

Hildebrandt

et al. 1991

Antimicrob Agents Chemother

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SDZ MRL 953, a new synthetic monosaccharidic lipid A, was investigated in vitro and in vivo for immunopharmacological activities. In experimental models of microbial infections, the compound was highly protective when it was administered prophylactically either once or three times to myelosuppressed or immunocompetent mice. The 50% effective doses of SDZ MRL 953 varied with the infectious agents and the route of its administration. In all cases, the 50% effective doses were about 103 times higher than those obtained with endotoxin from Salmonella abortus equi. SDZ MRL 953 was, however, less toxic than lipopolysaccharide by a factor of 104 to >7 x 105 times in galactosamine-sensitized mice. The compound was also an effective inducer of tolerance to endotoxin. Hence, repeated dosing with the compound induced a transient resistance (.1 week) to lethal challenges with endotoxin. In vitro, the compound was devoid of intrinsic antimicrobial activity, but it moderately induced the release of cytokines from monocytes and primed human neutrophils for the enhanced production of reactive oxygen metabolites in response to a soluble stimulus. The results presented here suggest that SDZ MRL 953 may be useful in a clinical setting for enhancing resistance to infections, particularly in patients undergoing myelosuppressive chemotherapy or irradiation, and for the prophylaxis of endotoxin shock.Lipopolysaccharides (LPS) are common constituents of cell walls of gram-negative bacteria. They can cause a whole array of pathophysiological effects and are also the most powerful immunostimulants known. It is generally accepted that the lipid A moiety, the terminal acylated P(1-6)glucosamine disaccharide-1,4'-diphosphates of endotoxin, is responsible for immunopharmacological activity and induction of endotoxicity, such as changes in leukocyte count, disseminated intravascular coagulation, and multiorgan failure leading to irreversible shock and death (5,21,25).Extensive studies have unsuccessfully addressed the possibility of harnessing the immunopharmacological activities of endotoxins by using various detoxifying approaches (17,20). The elucidation of the correct structure of lipid A (8, 26) and the subsequent success in the total synthesis of biologically active lipid A and analogs (9-12, 27) have rekindled interest in the possibility of separating the immunostimulatory and toxic moieties of endotoxin. Efforts to identify beneficial immunostimulatory lipid A derivatives have concentrated on synthetic analogs representing both the nonreducing (10-12) and reducing sugar moieties, such as lipids X and Y (15,27). Synthetic lipid A subunits of the nonreducing sugar moiety such as GLA-27 and GLA-60 were reported to activate B cells and macrophages and to induce release of mediators including gamma interferon and tumor necrosis factor (TNF) at nontoxic doses (for a review, see reference 5). The analogs were also found to be active in enhancing host resistance to microbial and viral infections in normal and myelosuppressed mice (5-7). Synth...

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“…C57BL/6 and ICR mice, 7-10 weeks old, were purchased from Shizuoka Laboratory Animal Center, Hamamatsu, Japan. Mice were maintained in the Laboratory of Animal Experiments, the Institute of Immunological subunit analogs, GLA-27, -59 and -60, were chemically synthesized according to the methods described previously [17,18]. The purity of the synthetic analogs was more than 99%.…”

Section: Methodsmentioning

confidence: 99%

Induction of an endogenous tumor necrosis factor in mice by murine recombinant interferon-? combined with a lipid A subunit analog (GLA-60) of low toxicity

Saiki

Maeda

Sakurai

et al. 1989

Cancer Immunol Immunother

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We have investigated the endogenous production of a serum cytotoxic factor when recombinant interferon-gamma (rIFN-gamma) is combined with synthetic lipid A subunit analogs of low toxicity (GLA compounds). The cytotoxic activity of the serum was measured by the crystal violet staining method with L929 cells as a target. Intravenous administration of rIFN-gamma followed by intravenous administration of lipopolysaccharide induced the endogenous production of a cytotoxic factor in the serum. The priming effect of rIFN-gamma appeared immediately and persisted for approximately 20 h after the injection. Administration of lipopolysaccharide as a trigger enhanced the production of the cytotoxic factor in the serum maximally 2 h after the injection. The cytotoxic activity in the serum was completely inhibited by anti-(mouse tumor necrosis factor) (TNF) antibody. A synthetic lipid A subunit analog (GLA-60), which is much less toxic in its endotoxin activities than lipopolysaccharide or synthetic lipid A (compound 506), induced the endogenous production of serum TNF in rIFN-gamma-primed mice. GLA-60 entrapped within liposomes induced the production of serum TNF in rIFN-gamma-primed mice more effectively than GLA-60 solubilized in phosphate-buffered saline. Intravenous or intranasal administrations of rIFN-gamma followed by intranasal administration of GLA-60 produced TNF in the lung washing fluid but not in the serum, indicating that TNF production can be induced locally rather than systemically by the alteration of the administration route of the primer and trigger. These results indicate that GLA-60, a lipid A subunit analog of low toxicity, is a beneficial triggering agent in the production of endogenous TNF, as well as having other immunopharmacological properties, and may provide a basis for cancer (metastases) treatment as a result of its ability to induce endogenous TNF.

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Synthesis of 2-deoxy-4-O-phosphono-3-O-tetradecanoyl-2-[(3R- and (3S)-3-tetradecanoyloxytetradecanamido]-d-glucose: a diastereoisomeric pair of 4-O-phosphono-d-glucosamine derivatives (GLA-27) related to bacterial lipid A

Cited by 32 publications

References 35 publications

3-O-Desacyl Monophosphoryl Lipid A Derivatives: Synthesis and Immunostimulant Activities

3-O-Desacyl Monophosphoryl Lipid A Derivatives: Synthesis and Immunostimulant Activities

SDZ MRL 953, a novel immunostimulatory monosaccharidic lipid A analog with an improved therapeutic window in experimental sepsis

Induction of an endogenous tumor necrosis factor in mice by murine recombinant interferon-? combined with a lipid A subunit analog (GLA-60) of low toxicity

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