Kotani S, Takada H, Takahashi I, Tsujimoto M, Ogawa T, Ikeda T, Harada K, Okamura H, Tamura T, Tanaka S
Infect Immun. 1986 Jun;52(3):872-84. doi: 10.1128/iai.52.3.872-884.1986.
A synthetic lipid A (Salmonella type, compound 516), beta (1-6)-linked D-glucosamine disaccharide 1,4'-bisphosphate, with three acyloxyacyl groups and one hydroxyacyl group, i.e., (R)-3-hexadecanoyloxytetradecanoyl, (R)-3-hydroxytetradecanoyl, (R)-3-dodecanoyloxytetradecanoyl, and (R)-3-tetradecanoyloxytetradecanoyl groups at the 2-amino, 3-hydroxyl, 2'-amino, and 3'-hydroxyl groups, respectively, was less biologically active than the synthetic Escherichia coli-type lipid A (compound 506), which has only two acyloxyacyl groups at the 2' and 3' positions and is substituted with a (R)-3-hydroxytetradecanoyl group at the 2-amino group. Compound 516 exhibited considerably weaker pyrogenic and leukopenic activity than compound 506, and it scarcely prepared rabbit skin for the Shwartzman reaction and lacked lethal toxicity on chicken embryos, although its lethal toxicity in galactosamine-loaded mice was as strong as that of compound 506. Compound 516 was also less active than compound 506 or natural E. coli lipid A (from Restrain F515) in other biological test systems, such as the Limulus test, stimulation of macrophages and lymphocytes, and interferon-inducing activity but not for interleukin-1 induction or complement activation. This observation suggests that there is an optimal number of acyloxyacyl groups on the glucosamine backbone for producing the biological activities of lipid A, especially the endotoxic activities. The 4'-monophosphate analog (compound 514) of compound 516 in general had significantly weaker activity than compound 516 in the above assays, most probably because of its greater hydrophobicity and consequently lower solubility in assay systems. Bacterial R595 lipid A derived from S. minnesota Re-mutant, which is a mixture of compounds 516 and 506, their 4'-monophosphate analogs and other compounds, exerted intermediate degrees of activity between compounds 506 and 516 in the various test systems employed.
一种合成脂质A（沙门氏菌型，化合物516），即β(1-6)连接的D-葡糖胺二糖1,4'-二磷酸，在2-氨基、3-羟基、2'-氨基和3'-羟基上分别带有三个酰氧基酰基和一个羟基酰基，即(R)-3-十六烷酰氧基十四烷酰基、(R)-3-羟基十四烷酰基、(R)-3-十二烷酰氧基十四烷酰基和(R)-3-十四烷酰氧基十四烷酰基，其生物活性低于合成的大肠杆菌型脂质A（化合物506），后者在2'和3'位仅具有两个酰氧基酰基，且在2-氨基上被一个(R)-3-羟基十四烷酰基取代。化合物516的致热和白细胞减少活性明显弱于化合物506，它几乎不能使兔皮对施瓦茨曼反应产生反应，并且对鸡胚没有致死毒性，尽管其在半乳糖胺负荷小鼠中的致死毒性与化合物506一样强。在其他生物测试系统中，如鲎试剂试验、巨噬细胞和淋巴细胞的刺激以及干扰素诱导活性方面，化合物516也比化合物506或天然大肠杆菌脂质A（来自Restrain F515）活性低，但在白细胞介素-1诱导或补体激活方面并非如此。这一观察结果表明，在葡糖胺主链上存在一个产生脂质A生物活性，尤其是内毒素活性的最佳酰氧基酰基数。化合物516的4'-单磷酸类似物（化合物514）在上述测定中一般比化合物516的活性明显弱，最可能的原因是其疏水性更强，因此在测定系统中的溶解度更低。源自明尼苏达沙门氏菌Re-突变体的细菌R595脂质A，它是化合物516和506、它们的4'-单磷酸类似物及其他化合物的混合物，在所采用的各种测试系统中表现出介于化合物506和516之间的中等活性程度。
