期刊
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
卷 2010, 期 1, 页码 80-91出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/ejoc.200900973
关键词
Carbohydrates; Lipids; Lipopolysaccharides; Immunochemistry; Cytokines; Protecting groups; Adjuvant; Tumor necrosis factor; Inflammation
资金
- National Institutes of Health (NIH) [R01GM061761]
- National Cancer Institute (NCI) [R01CA088986]
- Dr I. Toth (University of Queensland)
- Francine Kroesen
- Arlo D. Harris
- UQ-GSRTG
- NATIONAL CANCER INSTITUTE [R01CA088986] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM061761] Funding Source: NIH RePORTER
Lipopolysaccharides (LPS), which are structural components of the outer-surface membrane of Gram-negative bacteria, trigger innate immune responses through activation of Toll-like receptor 4 (TLR4). Such responses may be exploited for the development of adjuvants and in particular monophosphoryl lipid A (MPLA) obtained by controlled hydrolysis of LPS of Salmonella minnesota, exhibits low toxicity yet possesses beneficial immuno-stimulatory proper-ties. We have developed an efficient synthetic approach for the preparation of a major component of MPLA (1), which has as a key feature the use of allyloxycarbonates (Alloc) as permanent protecting groups for the C-3 and C-4 hydroxy groups of the proximal glucosamine unit. The latter protecting groups greatly facilitated deprotection of the fully assembled compound. Furthermore, the amino functions were protected as N-2,2,2-trichloroethoxycarbamates (Troc), which performed efficient neighboring-group participation to give selectively 1,2-trans-glycosides and could easily be removed under mild conditions without affecting the permanent Alloc carbonates and anomeric dimethylthexylsilyl (TDS) ether. The synthetic methodology was also employed for the preparation of a monophosphoryl lipid A (2) derivative that has the anomeric center of the proximal sugar modified as a methyl glycoside. Compound 1 was not able to induce cytokine production in mouse macrophages whereas methyl glycoside 2 displayed activity, however it has a lower potency and efficacy than lipid A obtained by controlled hydrolysis S. minnesota. This indicates compound 2 is an attractive candidate for adjuvant development and that 1 is not the active substance of MPLA obtained by controlled hydrolysis of LPS.
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