3-O-desacyl monophosphoryl lipid a derivatives:: Synthesis and immunostimulant activities

被引：83

作者：

Johnson, DA ^{[1
]}

Keegan, DS ^{[1
]}

Sowell, CG ^{[1
]}

Livesay, MT ^{[1
]}

Johnson, CL ^{[1
]}

Taubner, LM ^{[1
]}

Harris, A ^{[1
]}

Myers, KR ^{[1
]}

Thompson, JD ^{[1
]}

Gustafson, GL ^{[1
]}

Rhodes, MJ ^{[1
]}

Ulrich, JT ^{[1
]}

Ward, JR ^{[1
]}

Yorgensen, YM ^{[1
]}

Cantrell, JL ^{[1
]}

Brookshire, VG ^{[1
]}

机构：

[1] RIBI Immunochem Res Inc, Div Pharmaceut Discovery, Hamilton, MT 59840 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1999年 / 42卷 / 22期

关键词：

D O I：

10.1021/jm990222b

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The synthesis of a series of novel analogues of lipid A, the active principle of lipopolysaccharide, is reported. In these compounds, the 1-O-phosphono and (R)-3-hydroxytetradecanoyl moieties of native Salmonella minnesota R595 lipid A have been replaced with hydrogen and the length of the normal fatty acyl residues has been systematically varied. Normal fatty acid chain length in the 3-O-desacyl monophosphoryl lipid A (MLS) series is shown to be a critical determinant of iNOS gene expression in activated mouse macrophages and the induction of proinflammatory cytokines in human peripheral monocytes. Examination of pyrogenicity in rabbits and lethal toxicity in D-galactosamine-treated mice shows that toxic effects in the MLA series can be ameliorated by modifying fatty acid chain length. When used as an adjuvant for tetanus toroid vaccines, certain MLA derivatives enhance the production of tetanus toroid-specific antibodies in mice.

引用

页码：4640 / 4649

页数：10

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