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M Kiso

Publications and source records attributed to M Kiso.

At least 145 records · Page 8Linked to original sources
PubMed1991

Inhibition in mice of experimental metastasis of B16 melanoma by the synthetic lipid A-subunit analogue GLA-60.

Antimetastatic effects of the monosaccharic lipid A-subunit analogue GLA-60 against B16-F10 melanomas were investigated. Intravenous injection of 10 micrograms GLA-60 one day or two days before transplantation of 10(5) melanoma cells resulted in a significant decrease in the number of melanoma colonies metastasized into the lung. Intramuscular injection was also effective. Oral administration as well as intraperitoneal and subcutaneous administrations of 100 micrograms GLA-60 were also effective in preventing metastasis of the melanoma. However, these prophylactic effects of GLA-60 on the metastasis were diminished in mice which had been pre-treated with anti-asialo GM1 serum; on the other hand, prophylaxis was not affected in mice pre-treated with anti-Mac 1 antibody. These results suggest that asialo GM1 positive cells, probably natural killer cells, but not macrophages, participate as effector cells in depressing metastasis of the melanoma cells into the lung. In addition, GLA-60 also showed therapeutic potency in depressing metastasis, under a defined condition. The antimetastatic effect of GLA-60 was compared with other immunomodulators.

Adjuvants, Immunologic↗
PubMed1991

Effect of methyl esterification of isoglutamine residue in 6-O-acylated muramyl dipeptides on expression of immunopharmacological activities.

The effect of methyl esterification of the isoglutamine residue in 6-O-acylated muramyl dipeptide (MDP) on some biological activities was investigated. Methyl esterification influenced more or less the expression of all activities tested. The adjuvant and colony stimulating factor (CSF)-inducing activities of 6-O-acylated MDP analogs carrying a 3-hexadecanoyloxytetradecanoyl [C14-O-(C16)] group were stronger than those of the corresponding analogs carrying a 2-tetradecylhexadecanoyl (B30) group. Macrophage activation, i.e. induction of tumor necrosis factor (TNF) and promotion of phagocytosis, by 6-O-C14-O-(C16)-MDP methyl esters was weaker.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1990

Stereoselective synthesis of sialyl-lactotetraosylceramide and sialylneolactotetraosylceramide.

The first total syntheses of sialyl-lactotetraosylceramide (28, IV3NeuAcLc4Cer) and sialylneolactotetraosylceramide (32, IV3NeuAcnLc4Cer) are described. Methyl O-(methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero- alpha-D-galacto-2-nonulopyranosylonate)-(2----3)-2,4,6-tri-O-benzo yl-1-thio- beta-D-galactopyranoside (4), the key glycosyl donor, was prepared from 2-(trimethylsilyl)ethyl O-(methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-alpha-D-galacto -2- nonulopyranosylonate)-(2----3)-6-O-benzoyl-beta-D-galactopyranosid e (1), via benzoylation, replacement of the 2-(trimethylsilyl)ethyl group by acetyl, and introduction of the methylthio group with methylthiotrimethylsilane. Coupling of 2-(trimethylsilyl) ethyl 2,3,6,2',4',6'-hexa-O-benzyl-beta-D-lactoside (8), prepared from 2-(trimethylsilyl)ethyl beta-D-lactoside (5) via selective 3'-O-(4-methoxybenzylation), benzylation, and selective removal of the 4-methoxybenzyl group, with 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-D-glucopyranosyl bromide (9) gave a trisaccharide derivative 10, from which the phthaloyl and O-acetyl groups were removed. N-Acetylation then gave 2-(trimethylsilyl)ethyl O-(2-acetamido-2-deoxy-beta-D-glucopyranosyl)-(1----3)-O-(2,4,6-tri-O-be nzyl- beta-D-galactopyranosyl)-(1----4)-2,3,6-tri-O-benzyl-beta-D-glucopyranos ide (12). Dimethyl(methylthio)sulfonium triflate-promoted coupling of 4 with 13, prepared from 12 by 4,6-O-benzylidenation, or with 15, obtained from 13 by O-(4-methoxybenzylation) and reductive opening of the benzylidene acetal, gave the corresponding pentasaccharide derivatives 16 and 20 in good yields. Compounds 16 and 20 were converted into the corresponding alpha-trichloroacetimidates 19 and 23 which, on coupling with (2S,3R,4E)-2-azido-3-O-benzoyl-4-octadecene-1,3-diol (24), gave the beta-glycosides 25 and 29, respectively. Finally, 25 and 29 were transformed, via selective reduction of the azide group, condensation with octadecanoic acid, O-deacylation, and hydrolysis of the methyl ester group, into 28 and 32, respectively.

Carbohydrate Sequence↗
PubMed1990

Synthesis of alpha-Kdo-(2----4)-Kdo disaccharide derivatives and their conjugation with a protected form of GLA-60, a biologically active analog of a lipid A subunit.

A variety of the protected O-[(3-deoxy-alpha-D-manno-2-octulopyranosyl)onic acid]-(2----4)-3-deoxy-D-manno-2-octulosonic acid [alpha-Kdo-2(2----4)-Kdo] derivatives have been synthesized starting from methyl [2-(trimethylsilyl)ethyl 4,5,7,8-tetra-O-acetyl-3-deoxy-alpha-D-manno-2-octulopyranosid] onate. Some of these were conjugated with a protected form of a bacterial lipid A subunit-analog (GLA-60) having beneficial immunopharmacological activity, namely benzyl 2-[(3R)-3-(benzyloxy-methoxy)tetradecanamido]-2-deoxy-4-O- (diphenoxyphosphinyl)3-O-[(3R)-3-tetradecanoyloxytetradecanoyl+ ++]-beta -D-glucopyranoside.

Carbohydrate Sequence↗
PubMed1990

New ganglioside analogs that inhibit influenza virus sialidase.

Synthetic thioglycoside-analogs of gangliosides such as Neu5Ac alpha(2-S-6)Glc beta(1-1)Ceramide (1) and the GM3 analog Neu5Ac alpha(2-S-6)Gal beta(1-4)Glc beta(1-1)Ceramide (2), competitively inhibited GM3 hydrolysis by the sialidase of different subtypes of human and animal influenza viruses with an apparent Ki value of 2.8 x 10(-6) and 1.5 x 10(-5) M, respectively. The inhibitory activity of the ganglioside GM4 analog [Neu5Ac alpha(2-S-6)Gal beta(1-1)Ceramide (3)], in which the glucose of 1 was substituted by galactose, was lower than that of 1 (Ki = 1.0 x 10(-4) M). The thioglycoside-analogs (1, 2, 3) of the gangliosides were non-hydrolyzable substrates for influenza virus sialidase. The inhibitory activity of 1 to bacterial sialidases from Clostridium perfringens and Arthrobacter ureafaciens was considerably lower than that to influenza virus sialidase, indicating that the structure of the active site in bacterial and influenza virus sialidase may be different and the analogs may be useful to determine the orientation of the substrate to the active site of sialidases, especially of influenza viruses.

Carbohydrate Sequence↗
PubMed1990

Effect of acyl substituents of synthetic lipid A-subunit analogues on their immunomodulating antiviral activity.

A chemically synthesized lipid A-subunit analogue, GLA-60, 2-deoxy-4-O-phosphono-2-[(3R)-3-hydroxytetradecanamido]-3-O-[(3R)- 3- tetradecanoyloxytetradecanoyl]-D-glucose, has many of the activities of endotoxin but has little toxicity. Then, compounds with various lengths of acyl side chain of the acyloxyacyl group at the 3-O position of GLA-60 were synthesized and evaluated for interferon (IFN)-inducing activity, natural killer (NK) cell activation and antiviral activity. The compounds with acyl side chains between C8 and C15 exhibited significant antiviral activity (inhibition of pox tail lesion formation in vaccinia virus-infected mice), serum IFN-inducing activity and NK cell activation. However, the compound carrying a C2 or a C16 acyl side chain did not exhibit these activities. The compounds with a C13 or C14 acyl side chain showed strong protective against herpes simplex virus type 1 in cyclophosphamide-immunosuppressed mice.

Acylation↗
PubMed1990

Production of interleukin 1 from human monocytes stimulated by synthetic lipid A subunit analogues.

We have investigated that synthetic lipid A subunit analogues (GLA compounds) as well as E. coli type lipopolysaccharide (LPS) and synthetic lipid A (compound 506) are able to stimulate human monocytes to release IL-1 in vitro. Of monosaccharide-type GLA compounds, GLA-60 was found to be more active for the induction of IL-1 production than GLA-59 and GLA-27, and similar to that of LPS or compound 506. GLA-60 could induce not only the secretion of IL-1 into culture supernatant but also the expression of membrane-associated form of IL-1 in human monocytes. Furthermore, no detectable IL-2 activity was observed in the culture supernatant. These results show that synthetic lipid A analogues of low toxicity, in particular GLA-60, are active in inducing IL-1 production in human monocytes.

Cell Division↗
PubMed1990

Enhancement of nonspecific resistance to microbial infections of synthetic lipid A-subunit analogues of GLA-27 modified at the C1 position of the glucosamine backbone.

The C1 position of lipid A-subunit analogue GLA-27, 4-O-phosphono-D-glucosamine carrying N-3-tetradecanoyloxytetradecanoyl(C14-O-(C14)) and 3-O-tetradecanoyl (C14) groups, was S-acetylated, thiolated or phosphorylated. Enhancement of nonspecific resistance to Pseudomonas aeruginosa and vaccinia virus infections of these chemically modified compounds were investigated. Thiolation augmented the nonspecific resistance to P. aeruginosa infection. Protective activity against vaccinia virus infection was reduced by all the chemical modifications. NK cell activity was found not to be effected by S-acetylation, but to be decreased slightly by thiolation or phosphorylation. IFN-inducing activity was reduced remarkably by thiolation or S-acetylation, or completely diminished by phosphorylation, compared with that of GLA-27.

Animals↗
PubMed1990

Activation by synthetic lipid A subunit analogues (GLA compounds) of tumoricidal properties in human blood monocytes.

The authors have determined that synthetic lipid A subunit analogues (GLA compounds), as well as E. coli type lipopolysaccharide (LPS) and synthetic lipid A (compound 506), are able to stimulate human monocytes to become cytotoxic against tumour target cells in vitro. GLA-60, a synthetic lipid A subunit analogue of low toxicity, was found to be more active for the induction of tumoricidal monocytes than GLA-59, and similar to that of LPS. GLA-60 could induce not only the secretion of cytotoxic factor into the culture supernatant but also expression of the membrane-associated form of cytotoxic factor in human monocytes. Supernatant-mediated cytotoxicity was completely inhibited by the addition of monoclonal anti-human TNF antibody. These results indicate that a synthetic lipid A subunit analogue, GLA-60, would be a useful activator of tumoricidal monocytes in spite of its low toxicity.

Adjuvants, Immunologic↗
PubMed1990

Non-specific protective activity of synthetic lipid A-subunit analogs against microbial infections is influenced by their 2-N- and 3-O-linked acyl substituents in the D-glucosamine backbone.

Non-specific protective activities against vaccinia virus (VV) and Pseudomonas aeruginosa infections as well as interferon (IFN)-inducing, natural killer (NK) cell and macrophage activation activities of chemically synthesized lipid A-subunit analogs were investigated. The analogs are 4-O-phosphono-D-glucosamine derivatives carrying different 2-N- and 3-O-linked acyl substituents such as (R)-3-tetradecanoyloxytetradecanoyl (C14-O-(C14)), (R)-3-hydroxytetradecanoyl (C14-OH) and tetradecanoyl (C14) groups. Compounds GLA-59 and GLA-60, which possess C14-OH and C14-O-(C14) groups as their acyl substituents, showed stronger IFN-inducing and anti-vaccinia virus activities than GLA-27 and GLA-68, which possess a C14 group instead of the C14-OH group in GLA-59 and GLA-60, although NK cell activation activity was similarly high in all of these compounds. In protective activity against P. aeruginosa infection and macrophage activation activity, GLA-60 and GLA-68, which carry a C14-O-(C14) group at the 3-O-position, expressed higher activities than GLA-27 and GLA-59, which carry the acyloxyacyl group at the 2-N-position. These results indicate that the acyl substituent (whether the counterpart of the C14-O-(C14) group is a C14 or a C14-OH group) and the binding position of the acyloxyacyl group at the 2-N- or the 3-O-position strongly influence the manifestation of antimicrobial and immunomodulating activities in different ways depending on the activity. Among the compounds, GLA-60 satisfied the structure requirements for protection against both VV and P. aeruginosa infections. This compound is a hopeful immunomodulator for prevention against broad microbial infections.

Adjuvants, Immunologic↗
PubMed1989

Synthesis and immunoadjuvant activity of 2,2'-O-[2,2'-diacetamido-2,3,2',3'-tetradeoxy-6,6'-di-O-(2-tetradecyl- hexadecanoyl)-alpha,alpha'-trehalose-3,3'-diyl]bis(N-D-lactoyl-L-alanyl -D-isoglutamine).

The disaccharide of 6-O-(2-tetradecylhexadecanoyl)muramoyl dipeptide coupled through an alpha-(1----1)-alpha linkage, named in the title, and an analog bearing a single peptide moiety, have been synthesized from 2,2'-diazido-2,2'-dideoxy-alpha,alpha'-trehalose. The immunoadjuvant activities of the products were examined.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1989

A facile, regio- and stereo-selective synthesis of ganglioside GM3.

Gangliosides GM3, containing three different fatty acyl groups at the ceramide moiety, have been synthesized. Coupling of 2-(trimethylsilyl)ethyl O-(6-O-benzoyl-beta-D-galactopyranosyl)-(1----4)- 2,6-di-O-benzoyl-beta-D-glucopyranoside (4), prepared from 2-(trimethylsilyl)ethyl beta-lactoside (1) by selective 3'-O-benzylation, O-benzoylation, and subsequent removal of the benzyl group, with methyl (methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-2-thio-D-glycero-alpha-D- galacto - 2-nonulopyranosid)onate (5) using dimethyl(methylthio)sulfonium triflate as a glycosyl promoter, gave 2-(trimethylsilyl)ethyl O-(methyl 5-acetamido-4,7,8,9-tetra-O- acetyl-3,5-dideoxy-D-glycero-alpha-D-galacto-2-nonulopyranosylonate++ +)-(2----3)- O-(6-O- benzoyl-beta-D-galactopyranosyl)-(1----4)-2,6-di-O-benzoyl-beta-D- glucopyranoside (6), which was converted, via O-acetylation, selective removal of the 2-(trimethylsilyl)-ethyl group, and subsequent imidate formation, into the alpha-N-acetylneuraminyl-(2----3')-lactose trichloroacetimidate 9. Glycosylation of (2S,3R,4E)-2-azido-3-O-benzoyl-4-octadecene-1,3-diol (10) with 9 afforded the beta-glycoside 11, which was converted, via selective reduction of the azide group, coupling with fatty acids, O-deacetylation, and de-esterification, into the title compounds.

Carbohydrate Conformation↗