Synthesis and biological evaluation of Rhizobium sin-1 lipid A derivatives
Synthesis and biological evaluation of Rhizobium sin-1 lipid A derivatives
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DOI：
10.1021/ja029316s
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发表时间：
2003-05-21
影响因子：
15
通讯作者：
Boons, GJ
中科院分区：
文献类型：
--
作者：
Demchenko, AV;Wolfert, MA;Boons, GJ
一个高度收敛的策略，合成几个衍生物的根瘤菌sin-1的脂质A已经开发。该方法采用了高级中间体3-O-乙酰基-6-O-（3-O-乙酰基-4，6-O-亚苄基-2-脱氧-2-邻苯二甲酰亚氨基-β-D-吡喃葡萄糖基）-2-叠氮基-4-O-苄基-2-脱氧-1-硫代-α-D-吡喃葡萄糖苷（5），其以异头中心、C-2和C-2'氨基以及C-3和C-3'羟基可以选择性官能化的方式进行保护。该合成策略用于制备2-脱氧-6-O-12-脱氧-3-O-[（R）-3-羟基-十六烷酰基]-2-[（R）-3-二十八烷酰氧基-十六烷]酰氨基-β-D-吡喃葡萄糖基}-2-[（R）-3-羟基-十六烷]酰氨基-3-O-[（R）-3-羟基-十六烷酰基]-α-D-吡喃葡萄糖（11）和2-脱氧-6-O-{2-脱氧-3-O[（R）-3-羟基-十六烷酰基]-2-[（R）-3-羟基-十六烷酰基]-2-[（R）-3-羟基-十六烷酰基]-β-D-吡喃葡萄糖基}-2-[（R）-3-羟基-十六烷]酰氨基-3-O-[（R）-3-羟基-十六烷酰基]-α-D-吡喃葡萄糖（11）。3-二十八烷酰氧基-十六烷]酰氨基-D-吡喃葡萄糖基}-2-[（R）-3-羟基-十六烷]酰氨基-3-O-[（R）-3-羟基-十六烷酰基]-D-吡喃-1，5-内酯（13），其含有不寻常的二十八烷酸部分，并且异头中心的氧化态不同。生物学研究结果表明，11和13缺乏大肠杆菌脂多糖（LPS）的促炎作用。此外，13个仿真异构R. sin-1 LPS拮抗肠内LPS的作用，为R. sin-1 LPS介导这种拮抗作用。化合物13是脂质A衍生物的第一个实例，其不含磷酸盐，但具有拮抗性质，使其成为开发用于治疗革兰氏阴性败血症的药物的有吸引力的先导化合物。
A highly convergent strategy for the synthesis of several derivatives of the lipid A of Rhizobium sin-1 has been developed. The approach employed the advanced intermediate 3-O-acetyl-6-O-(3-O-acetyl-4,6-O-benzylidene-2-deoxy-2-phthalimido-beta-D-glucopyrano-syl)-2-azido-4-O-benzyl-2-deoxy-1 -thio-alpha-D-glucopyranoside (5), which is protected in such a way that the anomeric center, the C-2 and C-2' amino groups, and the C-3 and C-3' hydroxyls can be selectively functionalized. The synthetic strategy was used for the preparation of 2-deoxy-6-O-12-deoxy-3-O-[(R)-3-hydroxy-hexadecanoyl]-2-[(R)-3-octacosanoyloxy-hexadecan]amido-beta-D-glucopyranosyl}-2-[(R)-3-hydroxy-hexadecan]amido-3-O-[(R)-3-hydroxy-hexadecanoyl]- alpha-D-glucopyranose (11) and 2-deoxy-6-O-{2-deoxy-3-O[(R)-3-hydroxy-hexadecanoyl]-2-[(R)-3-octacosanoyloxy-hexadecan]amido-D-glucopyranosyl}-2-[(R)-3-hydroxy-hexadecan]amido-3-O-[(R)-3-hydroxy-hexadecanoyl]-D-glucono-1,5-lactone (13), which contain an unusual octacosanoic acid moiety and differ in the oxidation state of the anomeric center. The results of biological studies indicate that 11 and 13 lack the proinflammatory effects of Escherichia coli lipopolysaccharicles (LPS). Furthermore, 13 emulated the ability of heterogeneous R. sin-1 LPS to antagonize enteric LPS, providing evidence for the critical role of the gluconolactone moiety of R. sin-1 LPS in mediating this antagonistic effect. Compound 13 is the first example of a lipid A derivative that is devoid of phosphate but possesses antagonistic properties, making it an attractive lead compound for development of a drug to use in the treatment of Gram-negative septicemia.