Synthesis of 13C-Labeled Biosynthetic Precursor of Lipid A and Its Analogue with Shorter Acyl Chains

Oikawa, Masato; Shintaku, Tetsuya; Sekljic, Harald; Fukase, Koichi; Kusumoto, Shoichi

doi:10.1246/bcsj.72.1857

Cited by 22 publications

(30 citation statements)

References 18 publications

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“…Next, the isopropylidene acetal and anomeric TDS of 21 were removed by treatment with TFA/ H 2 O (3/2, v/v) in DCM and the anomeric hydroxyl of the resulting compound was regioselectively phosphorylated using tetrabenzyl diphosphate in the presence of lithium bis (trimethyl)silylamide in THF at −78°C [39] to give anomeric phosphate 22 as only the α-anomer. Finally, global deprotection of 22 could easily be accomplished by catalytic hydrogenolysis over Pd-black to give target product 3.…”

Section: Chemical Synthesismentioning

confidence: 99%

“…The removal of the Alloc protecting group of 24 could easily be accomplished by treatment with Pd (PPh 3 ) 4 and the hydroxyl group of the resulting compound 25 was acylated with (R)-2-benzyloxy-tetradecanoic acid (8) using DCC and DMAP as activating agents to afford fully acylated 26. The anomeric tert-butyldimethylsilyl (TBS) ether of 26 was removed by treatment with HF in pyridine and the resulting anomeric hydroxyl phosphorylated using tetrabenzyl diphosphate in the presence of lithium bis(trimethyl)silylamide in THF at −78°C [39] to give 27. Global deprotection of 27 by catalytic hydrogenolysis gave the requisite lipid A 1.…”

Section: Chemical Synthesismentioning

confidence: 99%

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Innate Immune Responses of Synthetic Lipid A Derivatives of Neisseria meningitidis

Zhang

Gaekwad

Wolfert

et al. 2007

Chemistry A European J

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Differences in the pattern and chemical nature of fatty acids of lipid A of Neisseria meningitides lipooligosaccharides (LOS) and Escherichia coli lipopolysaccharides (LPS) may account for differences in inflammatory properties. Furthermore, there are indications that dimeric 3-deoxy-Dmanno-oct-2-ulosonic acid (KDO) moieties of LOS and LPS enhance biological activities. Heterogeneity in the structure of lipid A and possible contaminations with other inflammatory components have made it difficult to confirm these observations. To address these problems, a highly convergent approach for the synthesis of a lipid A derivative containing KDO has been developed, which relies on the ability to selectively remove or unmask in a sequential manner an isopropylidene acetal, 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonate (Alloc), azide, and thexyldimethylsilyl (TDS) ether. The strategy was employed for the synthesis of N. meningitidis lipid A containing KDO (3). Mouse macrophages were exposed to the synthetic compound and its parent LOS, E. coli lipid A (2), and a hybrid derivative (4) that has the asymmetrical acylation pattern of E. coli lipid A, but the shorter lipids of meningococcal lipid A. The resulting supernatants were examined for tumor necrosis factor alpha (TNF-α) and interferon beta (IFN-β) production. The lipid A derivative containing KDO was much more active than lipid A alone and just slightly less active than its parent LOS, indicating that one KDO moiety is sufficient for full activity of TNF-α and IFN-β induction. The lipid A of N. meningitidis was a significantly more potent inducer of TNF-α and IFN-β than E. coli lipid A, which is due to a number of shorter fatty acids. The compounds did not demonstrate a bias towards a MyD88-or TRIF-dependent response.

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Section: Chemical Synthesismentioning

confidence: 99%

Section: Chemical Synthesismentioning

confidence: 99%

Innate Immune Responses of Synthetic Lipid A Derivatives of Neisseria meningitidis

Zhang

Gaekwad

Wolfert

et al. 2007

Chemistry A European J

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“…A fully protected equivalent of 1 was prepared first with full orthogonal protection (15, Scheme 2) and then sequentially de-protected and substituted. We prepared first the known key derivative 3 [18] from commercially available levoglucosan (overall yield 21%), using the method of Oikawa et al [19]. A first attempt to glycosylate 3 using tetraacetyl glucopyranose trichloroacetimidate [20] (8) in the presence of TMSOTf gave very little desired product 9, together with a large quantity of a side product identified as 1,6-anhydro-2-azido-3-O-benzyl-4-O-acetyl-2-deoxy-β-D-glucopyranose.…”

Section: Chemistrymentioning

confidence: 99%

“…(3). Compound 3 was synthesized in 7 steps (21% overall yield) from commercially available 1,6-anhydro-β-D-glucopyranose following the method of Oikawa et al [19]. Anhydro-2-azido-3-O-benzyl-2-deoxy-4-O-methyl-β-D-glucopyranose (4).…”

Section: General Informationmentioning

confidence: 99%

Investigating Glycol-Split-Heparin-Derived Inhibitors of Heparanase: A Study of Synthetic Trisaccharides

Elli

Naggi

et al. 2016

Molecules

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Abstract:Heparanase is the only known endoglycosidase able to cleave heparan sulfate. Roneparstat and necuparanib, heparanase inhibitors obtained from heparin and currently being tested in man as a potential drugs against cancer, contain in their structure glycol-split uronic acid moieties probably responsible for their strong inhibitory activity. We describe here the total chemical synthesis of the trisaccharide GlcNS6S-GlcA-1,6anGlcNS (1) and its glycol-split (gs) counterpart GlcNS6S-gsGlcA-1,6anGlcNS (2) from glucose. As expected, in a heparanase inhibition assay, compound 2 is one order of magnitude more potent than 1. Using molecular modeling techniques we have created a 3D model of 1 and 2 that has been validated by NOESY NMR experiments. The pure synthetic oligosaccharides have allowed the first in depth study of the conformation of a glycol-split glucuronic acid. Introducing a glycol-split unit in the structure of 1 increases the conformational flexibility and shortens the distance between the two glucosamine motives, thus promoting interaction with heparanase. However, comparing the relative activities of 2 and roneparstat, we can conclude that the glycol-split motive is not the only determinant of the strong inhibitory effect of roneparstat.

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“…To date, the anhydrosugar approach to 2-aminoglycosides has been applied to the synthesis of glycosaminoglycans, 162 GPI-anchored peptide, lipid A disaccharides, 165,166 N-acetyllactosamines, 167 and umbelliferone glycosides of N-acetyl glucosamine and chitobiose, 168 among others.…”

Section: From O-sulfonyl Derivativesmentioning

confidence: 99%

Recent trends in the synthesis of O-glycosides of 2-amino-2-deoxysugars

Bongat

Demchenko

2007

Carbohydrate Research

199

110

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Synthesis of 13C-Labeled Biosynthetic Precursor of Lipid A and Its Analogue with Shorter Acyl Chains

Cited by 22 publications

References 18 publications

Innate Immune Responses of Synthetic Lipid A Derivatives of Neisseria meningitidis

Innate Immune Responses of Synthetic Lipid A Derivatives of Neisseria meningitidis

Investigating Glycol-Split-Heparin-Derived Inhibitors of Heparanase: A Study of Synthetic Trisaccharides

Recent trends in the synthesis of O-glycosides of 2-amino-2-deoxysugars

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