186383-49-3Relevant academic research and scientific papers
Synthesis of monophosphoryl lipid A using 2-naphtylmethyl ethers as permanent protecting groups
Verpalen, Enrico C.J.M.,Brouwer, Arwin J.,Boons, Geert-Jan
, (2020/10/09)
Lipid A, which is a conserved component of lipopolysaccharides of gram-negative bacteria, has attracted considerable interest for the development of immuno-adjuvants. Most approaches for lipid A synthesis rely on the use of benzyl ethers as permanent protecting groups. Due to the amphiphilic character of lipid A, these compounds aggregate during the hydrogenation step to remove benzyl ethers, resulting in a sluggish reaction and by-product formation. To address this problem, we have developed a synthetic approach based on the use of 2-naphtylmethyl ether (Nap) ethers as permanent protecting group for hydroxyls. At the end of a synthetic sequence, multiple of these protecting groups can readily be removed by oxidation with 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ). Di-allyl N,N-diisopropylphosphoramidite was employed to install the phosphate ester and the resulting allyl esters were cleaved using palladium tetrakistriphenylphosphine. The synthetic strategy allows late stage introduction of different fatty acids at the amines of the target compound, which is facilitated by Troc and Fmoc as orthogonal amino-protecting groups.
The 'Ethereal' nature of TLR4 agonism and antagonism in the AGP class of lipid A mimetics
Bazin, Helene G.,Murray, Tim J.,Bowen, William S.,Mozaffarian, Afsaneh,Fling, Steven P.,Bess, Laura S.,Livesay, Mark T.,Arnold, Jeffrey S.,Johnson, Craig L.,Ryter, Kendal T.,Cluff, Christopher W.,Evans, Jay T.,Johnson, David A.
experimental part, p. 5350 - 5354 (2009/08/07)
To overcome the chemical and metabolic instability of the secondary fatty acyl residues in the AGP class of lipid A mimetics, the secondary ether lipid analogs of the potent TLR4 agonist CRX-527 (2) and TLR4 antagonist CRX-526 (3) were synthesized and evaluated along with their ester counterparts for agonist/antagonist activity in both in vitro and in vivo models. Like CRX-527, the secondary ether lipid 4 showed potent agonist activity in both murine and human models. Ether lipid 5, on the other hand, showed potent TLR4 antagonist activity similar to CRX-526 in human cell assays, but did not display any antagonist activity in murine models and, in fact, was weakly agonistic. Glycolipids 2, 4, and 5 were synthesized via a new highly convergent method utilizing a common advanced intermediate strategy. A new method for preparing (R)-3-alkyloxytetradecanoic acids, a key component of ether lipids 4 and 5, is also described.
New synthesis of glycolipid immunostimulants RC-529 and CRX-524
Bazin, Hélène G.,Bess, Laura S.,Livesay, Mark T.,Ryter, Kendal T.,Johnson, Craig L.,Arnold, Jeffrey S.,Johnson, David A.
, p. 2087 - 2092 (2007/10/03)
An efficient and scalable synthesis of the potent vaccine adjuvant RC-529 (3) and TLR4 agonist CRX-524 (4) is described in eight steps from 1,3,4,6-tetra-O-acetyl-2-amino-2-benzyloxycarbonyl-2-deoxy-β-d- glucopyranose (10c) in ca. 25% overall yield. The synthesis features the strategic use of the N-Cbz group for β-glycosylation and the selective N,N,O-triacylation of common advanced intermediate 15 with (R)-3- tetradecanoyloxy or decanoyloxytetradecanoic acid (8, 9) late in the synthesis. A new method for preparing and enhancing the enantiopurity of (R)-3-hydroxytetradecanoic acid (6), a key component of 3 and 4 as well as bacterial lipid A, is also described.
Aminoalkyl glucosaminide phosphate compounds and their use as adjuvants and immunoeffectors
-
, (2008/06/13)
Aminoalkyl glucosaminide phosphate (AGP) compounds that are adjuvants and immunoeffectors are described and claimed. The compounds have a 2-deoxy-2-amino glucose in glycosidic linkage with an aminoalkyl (aglycon) group. Compounds are phosphorylated at the 4 or 6 carbon on the glucosaminide ring and comprise three 3-alkanoyloxyalkanoyl residues. The compounds augment antibody production in immunized animals as well as stimulate cytokine production and activate macrophages. Compositions and methods for using the compounds as adjuvants and immunoeffectors are also disclosed.
Aminoalkyl glucosaminide phosphate compounds and their use as adjuvants and immunoeffectors
-
, (2008/06/13)
Aminoalkyl glucosaminide phosphate (AGP) compounds that are adjuvants and immunoeffectors are described and claimed. The compounds have a 2-deoxy-2-amino glucose in glycosidic linkage with an aminoalkyl (aglycon) group. Compounds are phosphorylated at the 4 or 6 carbon on the glucosaminide ring and comprise three 3- alkanoyloxyalkanoyl residues. The compounds augment antibody production in immunized animals as well as stimulate cytokine production and activate macrophages. Compositions and methods for using the compounds as adjuvants and immunoeffectors are also disclosed.
Aminoalkyl glucosamine phosphate compounds and their use as adjuvants and immunoeffectors
-
Page column 10, (2008/06/13)
Aminoalkyl glucosamine phosphate compounds that are adjuvants and immunoeffectors are described and claimed. The compounds have a 2-deoxy-2-amino glucose in glycosidic linkage with an aminoalkyl (aglycon) group. Compounds are phosphorylated at the 4 or 6 carbon on the glucosamine ring and comprise three 3-alkanoyloxyalkanoyl residues. The compounds augment antibody production in immunized animals as well as stimulate cytokine production and activate macrophages. Methods for using the compounds as adjuvants and immunoeffectors are also disclosed.
Aminoalkyl glucosaminide phosphate compounds and their use as adjuvants and immunoeffectors
-
, (2008/06/13)
Aminoalkyl glucosaminide phosphate (AGP) compounds that are adjuvants and immunoeffectors are described and claimed. The compounds have a 2-deoxy-2-amino glucose in glycosidic linkage with an aminoalkyl (aglycon) group. Compounds are phosphorylated at the 4 or 6 carbon on the glucosaminide ring and comprise three 3-alkanoyloxyalkanoyl residues. The compounds augment antibody production in immunized animals as well as stimulate cytokine production and activate macrophages. Methods for using the compounds as adjuvants and immunoeffectors are also disclosed.
Aminoalkyl glucosamine phosphate compounds and their use as adjuvants and immunoeffectors
-
, (2008/06/13)
Aminoalkyl glucosamine phosphate compounds that are adjuvants and immunoeffectors are described and claimed. The compounds have a 2-deoxy-2-amino glucose in glycosidic linkage with an aminoalkyl (aglycon) group. Compounds are phosphorylated at the 4 or 6 carbon on the glucosamine ring and comprise three 3-alkanoyloxyalkanoyl residues. The compounds augment antibody production in immunized animals as well as stimulate cytokine production and activate macrophages. Methods for using the compounds as adjuvants and immunoeffectors are also disclosed.
Efficient asymmetric synthesis of (R)-3-hydroxy- and alkanoyloxytetradecanoic acids and method for the determination of enantiomeric purity
Keegan, David S.,Hagen, Steven R.,Johnson, David A.
, p. 3559 - 3564 (2007/10/03)
An efficient synthesis of the (R)-3-hydroxy- and alkanoyloxytetradecanoic acid components of bacterial lipid A has been achieved using a Ru(II)-Binap-catalyzed low-pressure hydrogenation in the key step. The enantiomeric purity of p-bromophenacyl ester intermediate 4 could be assessed directly by chiral HPLC - obviating separate derivatization steps and/or chiral NMR shift studies.
