An improved synthesis of trehalose 6-mono and 6,6′-dicorynomycolates and related esters

Datta, Amlan; Takayama, K.; Nashed, Mina A.; Anderson, Louise E.

doi:10.1016/0008-6215(91)84089-w

Cited by 46 publications

(21 citation statements)

References 22 publications

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“…Glucose-3-O -monomycolate (G-3-MM) was synthesized using a similar strategy except that 4,6-O -benzylidene-1,2-O -isopropylidene derivative of glucose was used to couple via a 3-linkage. Synthetic C 32 mycolic acid was methylated and resolved in chloroform on preparative silica TLC plates to yield the 2 R , 3 R plus 2 S , 3 S enantiomeric pair with a retardation factor ( R f ) of 0.42, and the 2 R , 3 S plus 2 S , 3 R enantiomeric pair with an R f of 0.52, as determined by previous reports and comparison with methyl esters of the natural C 32 2 R , 3 R mycolate standard from R. equi (27). These mycolic acid methyl esters were glucosylated as described and used in T cell assays (27).…”

Section: Methodsmentioning

confidence: 92%

“…GMM yields were estimated by silica TLC developed in chloroform/methanol (90:8) and charred with cupric acetate solution at 160 Њ C for 15 min followed by computer-assisted densitometry (Scion Image Software) with quantitative standards. C 32 glucose-6-O -monomycolate (G-6-MM) was synthesized from 3-tert -butyldimethylsilylated mycolic acid and 1,2,3,4-tetra-O -tert -butyldimethylsilylated glucose as described (12,27). Glucose-3-O -monomycolate (G-3-MM) was synthesized using a similar strategy except that 4,6-O -benzylidene-1,2-O -isopropylidene derivative of glucose was used to couple via a 3-linkage.…”

Section: Methodsmentioning

confidence: 99%

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Cd1b-Mediated T Cell Recognition of a Glycolipid Antigen Generated from Mycobacterial Lipid and Host Carbohydrate during Infection

Moody

Guy

Grant

et al. 2000

The Journal of Experimental Medicine

139

107

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T cells recognize microbial glycolipids presented by CD1 proteins, but there is no information regarding the generation of natural glycolipid antigens within infected tissues. Therefore, we determined the molecular basis of CD1b-restricted T cell recognition of mycobacterial glycosylated mycolates, including those produced during tissue infection in vivo. Transfection of the T cell receptor (TCR) α and β chains from a glucose monomycolate (GMM)-specific T cell line reconstituted GMM recognition in TCR-deficient T lymphoblastoma cells. This TCR-mediated response was highly specific for natural mycobacterial glucose-6-O-(2R, 3R) monomycolate, including the precise structure of the glucose moiety, the stereochemistry of the mycolate lipid, and the linkage between the carbohydrate and the lipid. Mycobacterial production of antigenic GMM absolutely required a nonmycobacterial source of glucose that could be supplied by adding glucose to media at concentrations found in mammalian tissues or by infecting tissue in vivo. These results indicate that mycobacteria synthesized antigenic GMM by coupling mycobacterial mycolates to host-derived glucose. Specific T cell recognition of an epitope formed by interaction of host and pathogen biosynthetic pathways provides a mechanism for immune response to those pathogenic mycobacteria that have productively infected tissues, as distinguished from ubiquitous, but innocuous, environmental mycobacteria.

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Section: Methodsmentioning

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Cd1b-Mediated T Cell Recognition of a Glycolipid Antigen Generated from Mycobacterial Lipid and Host Carbohydrate during Infection

Moody

Guy

Grant

et al. 2000

The Journal of Experimental Medicine

139

107

View full text Add to dashboard Cite

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“…Synthesis of TDB 6,6 0 -diester analogues (TDX) Trehalose 6,6 0 -diesters were synthesized according to [26] by coupling fatty acids to the selectively protected a,a 0 -trehalose, i.e. 2,3,4,2 0 ,3 0 ,4 0 -hexa-O-(trimethylsilyl)-a,a-trehalose, in the presence of dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP).…”

Section: Synthesis Of Tdx Glycolipidsmentioning

confidence: 99%

“…TDB analogues were synthesized essentially as described previously [25][26][27] and incorporated into the bilayer of DDA liposomes by the thin-film method combined with probe sonication at a molar ratio of 11 mol% and characterized in terms of initial average particle size, PDI and zeta-potential ( Table 1). Incorporation of TDX did not significantly affect the average particle size of the resulting liposomes, as compared to DDA/TDB liposomes (140.3 ± 14.7 nm), which corresponds to previously reported values [29].…”

Section: Synthesis Of Tdx and Formulation Of Dda/tdx Liposomesmentioning

confidence: 99%

Influence of trehalose 6,6′-diester (TDX) chain length on the physicochemical and immunopotentiating properties of DDA/TDX liposomes

Kallerup

Madsen

Schiøth

et al. 2015

European Journal of Pharmaceutics and Biopharmaceutics

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“…To generate a simplified synthetic MMG analog, a 32 carbon mycolate analog was chosen; this choice corresponds to the mycolic acids of Corynebacterium diphtheriae whose synthesis has been previously described (19) (Fig. 4).…”

Section: The Potent Immunostimulatory Activity Can Be Mimicked By a Smentioning

confidence: 99%

A Simple Mycobacterial Monomycolated Glycerol Lipid Has Potent Immunostimulatory Activity

Andersen

Agger

Rosenkrands

et al. 2009

The Journal of Immunology

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It is a long held belief that the strong immunostimulatory activity of the Mycobacterium bovis bacillus Calmette-Guérin vaccine and Freund’s complete adjuvant is due to specific mycobacterial cell envelope components, such as lipids and polysaccharides. Implicated mycobacterial lipids include, among others, the so-called cord factor or trehalose dimycolate, but limited information is available regarding the precise molecular nature of the stimulatory components responsible for the interaction with human APCs. In this regard, the majority of research aimed at identifying and characterizing individual immunostimulatory mycobacterial lipids has been performed in the murine system using bone marrow-derived dendritic cells. In this study, it is documented that potent immunostimulatory activity lies within the bacillus Calmette-Guérin nonpolar lipid class. This activity can be narrowed down to a remarkably simple monomycolyl glycerol (MMG) with the ability to stimulate human dendritic cells as assessed by enhanced expression of activation markers and the release of proinflammatory cytokines. A synthetic analog of MMG based on 32 carbons (C32) was found to exhibit comparable levels of immunostimulatory activities. Immunization of mice with the tuberculosis vaccine candidate, Ag85B-ESAT-6, in MMG or the synthetic analog using cationic liposomes as the delivery vehicle was found to give rise to a prominent Th1 response characterized by significant levels of IFN-γ. Together, this development opens up the possibility of producing a novel class of chemically defined lipid adjuvants to enhance the activity of new vaccine formulations, directed against infectious agents including tuberculosis.

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An improved synthesis of trehalose 6-mono and 6,6′-dicorynomycolates and related esters

Cited by 46 publications

References 22 publications

Cd1b-Mediated T Cell Recognition of a Glycolipid Antigen Generated from Mycobacterial Lipid and Host Carbohydrate during Infection

Cd1b-Mediated T Cell Recognition of a Glycolipid Antigen Generated from Mycobacterial Lipid and Host Carbohydrate during Infection

Influence of trehalose 6,6′-diester (TDX) chain length on the physicochemical and immunopotentiating properties of DDA/TDX liposomes

A Simple Mycobacterial Monomycolated Glycerol Lipid Has Potent Immunostimulatory Activity

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