(R)-3-benzyloxyhexadecanoic acid | 548486-16-4

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: (R)-3-benzyloxyhexadecanoic acid
• 英文别名: (3R)-3-(Benzyloxy)hexadecanoic acid；(3R)-3-phenylmethoxyhexadecanoic acid
• CAS: 548486-16-4
• 化学式: C₂₃H₃₈O₃
• 分子量: 362.553
• InChiKey: FYVSGVUZADHFLJ-JOCHJYFZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.8
• 重原子数：
  26
• 可旋转键数：
  17
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  46.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  Octacosanoic acid (R)-1-({(2R,4aR,6R,7R,8R,8aS)-6-[(2R,3S,4R,5S)-5-amino-2,3,4-tris-benzyloxy-6-(tert-butyl-diphenyl-silanyloxy)-hexyloxy]-8-hydroxy-2-phenyl-hexahydro-pyrano[3,2-d][1,3]dioxin-7-ylcarbamoyl}-methyl)-tetradecyl ester 、 (R)-3-benzyloxyhexadecanoic acid 在 4-二甲氨基吡啶 、 N,N'-二环己基碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 反应 16.0h， 以71%的产率得到1-O-(tert-butyldiphenylsilyl)-6-O-{4',6'-O-benzylidene-3'-O-[(R)-3-benzyloxyhexadecanoyl]-2'-deoxy-2'-[(R)-3-octacosanoyloxyhexadecan]amido-β-D-glucopyranosyl}-2-[(R)-3-benzyloxyhexadecan]amido-3,4,5-tri-O-benzyl-D-glucitol
  参考文献：
  名称：

  包含氨基葡萄糖酸酯部分的脂质A衍生物的合成和生物学评估。

  摘要：

  已经开发出用于合成根瘤菌Sin-1的脂质A的几种衍生物的高度收敛的策略。合成的衍生物是2-氨基葡萄糖酸酯3和2-氨基葡萄糖酸内酯4，它们都没有C-3酰化。这些衍生物是通过制备二糖获得的，其中两个氨基和C-3'羟基可以分别用酰基或β-羟基脂肪酰基进行修饰。详细的NMR光谱和3和4的MS分析表明，即使在中性条件下，这两种化合物也会达到平衡。如不存在肿瘤坏死因子的产生所表明的，合成的化合物缺乏大肠杆菌脂多糖（LPS）的促炎作用。尽管3和4能够拮抗大肠杆菌LPS，但它们的效力远低于合成化合物2，在C-3和R. sin-1 LPS上被酰化；这些结果表明，C-3处的β-羟基脂肪酰基有助于R.sin-1LPS的拮抗性质。根据合成脂质A衍生物与R. sin-1 LPS和脂质A的生物学响应的比较，3-脱氧-D-甘露聚糖-八聚体部分对于肠道LPS的最佳拮抗作用似乎很重要。诱导的细胞因子产生。

  DOI：

  10.1002/chem.200400376
• 作为产物：
  描述：

  2,2,2-三氯乙酰胺苄酯 在 三氟甲磺酸 、 溶剂黄146 、 锌 作用下， 以 二氯甲烷 为溶剂， 反应 24.0h， 生成 (R)-3-benzyloxyhexadecanoic acid
  参考文献：
  名称：

  Synthesis and Biological Evaluation of Rhizobium sin-1 Lipid A Derivatives

  摘要：

  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.

  DOI：

  10.1021/ja029316s

文献信息

• Synthetic tetra-acylated derivatives of lipid A from Porphyromonas gingivalis are antagonists of human TLR4
  作者：Yanghui Zhang、Jidnyasa Gaekwad、Margreet A. Wolfert、Geert-Jan Boons

  DOI：10.1039/b809090d

  日期：——

  Tetra-acylated lipid As derived from Porphyromonas gingivalis LPS have been synthesized using a key disaccharide intermediate functionalized with levulinate (Lev), allyloxycarbonate (Alloc) and anomeric dimethylthexylsilyl (TDS) as orthogonal protecting groups and 9-fluorenylmethoxycarbamate (Fmoc) and azido as amino protecting groups. Furthermore, an efficient cross-metathesis has been employed for the preparation of the unusual branched R-(3)-hydroxy-13-methyltetradecanic acid and (R)-3-hexadecanoyloxy-15-methylhexadecanoic acid of P. gingivalislipid A. Biological studies have shown that the synthetic lipid As cannot activate human and mouse TLR2 and TLR4 to produce cytokines. However, it has been found that the compounds are potent antagonist of cytokine secretion by human monocytic cells induced by enteric LPS.

  来自牙龈卟啉单胞菌LPS的四酰化脂质A已通过使用关键的二糖中间体合成，该中间体功能化带有乙酰丙酸酯（Lev）、烯丙氧基碳酸酯（Alloc）和异头二甲基苯基硅烷（TDS）作为正交保护基团，以及9-芴甲氧基羰酰胺（Fmoc）和叠氮基作为氨基保护基团。此外，已采用高效的交叉复分解反应制备了牙龈卟啉单胞菌脂质A中不寻常的分支R-(3)-羟基-13-甲基十四烷酸和(R)-3-十六烷酰氧基-15-甲基十六烷酸。生物学研究显示，合成脂质A不能激活人体和小鼠的TLR2和TLR4以产生细胞因子。然而，研究发现这些化合物是肠道LPS诱导的人单核细胞分泌细胞因子的强效拮抗剂。
• Synthetic lipid A derivative
  申请人：University of Georgia Research Foundation, Inc.

  公开号：US09309276B2

  公开（公告）日：2016-04-12

  The invention provides functionalized monosaccharides and disaccharides suitable for use in synthesizing a lipid A derivative, as well as methods for synthesizing and using a synthetic lipid A derivative.

  这项发明提供了适用于合成脂多糖A衍生物的功能化单糖和双糖，以及合成和使用合成脂多糖A衍生物的方法。
• SYNTHETIC LIPID A DERIVATIVE
  申请人：Boons Geert-Jan

  公开号：US20100221269A1

  公开（公告）日：2010-09-02

  The invention provides functionalized monosaccharides and disaccharides suitable for use in synthesizing a lipid A derivative, as well as methods for synthesizing and using a synthetic lipid A derivative.

  这项发明提供了适用于合成脂多糖A衍生物的功能化单糖和双糖，以及合成和使用合成脂多糖A衍生物的方法。
• The influence of the long chain fatty acid on the antagonistic activities of Rhizobium sin-1 lipid A
  作者：Yanghui Zhang、Margreet A. Wolfert、Geert-Jan Boons

  DOI：10.1016/j.bmc.2007.05.012

  日期：2007.7

  27-hydroxyoctacosanoic acid for antagonistic properties, a highly convergent strategy for the synthesis of several derivatives of the lipid A of R. sin-1 has been developed. Compound 1 is a natural R. sin-1 lipid A having a 27-hydroxyoctacosanoic acid at C-2', compound 2 contains an octacosanoic acid moiety at this position, and compound 3 is modified by a short chain tetradecanoic acid. Cellular activation

  来自固氮细菌根瘤菌 sin-1 的脂质 A 在结构上是不寻常的，因为缺乏磷酸盐并且存在 2-氨基葡萄糖酸内酯和极长链脂肪酸 27-羟基二十八烷酸 (27OHC28:0) 部分。这种结构上不寻常的脂质 A 可以拮抗大肠​​杆菌 LPS 诱导的人单核细胞产生 TNF-α。为了确定不寻常的长链 27-羟基二十二烷酸与拮抗特性的相关性，开发了一种高度收敛的策略来合成 R. sin-1 的脂质 A 的几种衍生物。化合物1是在C-2'处具有27-羟基二十二烷酸的天然R.sin-1脂质A，化合物2在该位置含有二十八烷酸部分，并且化合物3被短链十四烷酸修饰。对人类单核细胞系的细胞活化研究表明，二十八烷酸对于最佳拮抗特性非常重要。然而，天然 27-羟基二十八烷酸部分的羟基并不能解释抑制活性。由此产生的结构-活性关系对于设计治疗感染性休克的化合物非常重要。
• Agonistic and antagonistic properties of a Rhizobium sin-1 lipid A modified by an ether-linked lipid
  作者：Mahalakshmi Vasan、Margreet A. Wolfert、Geert-Jan Boons

  DOI：10.1039/b704427e

  日期：——

  LPS from Rhizobiumsin-1 (R.sin-1) can antagonize the production of tumor necrosis factor alpha (TNF-α) by E. coli LPS in human monocytic cells. Therefore these compounds provide interesting leads for the development of therapeutics for the prevention or treatment of septic shock. Detailed structure activity relationship studies have, however, been hampered by the propensity of these compounds to undergo β-elimination to give biological inactive enone derivatives. To address this problem, we have chemically synthesized in a convergent manner a R.sin-1 lipid A derivative in which the β-hydroxy ester at C-3 of the proximal sugar unit has been replaced by an ether linked moiety. As expected, this derivative exhibited a much-improved chemical stability. Furthermore, its ability to antagonize TNF-α production induced by enteric LPS was only slightly smaller than that of the parent ester modified derivative demonstrating that the ether-linked lipids affect biological activities only marginally. Furthermore, it has been shown for the first time that R.sin-1 LPS and the ether modified lipid A are also able to antagonize the production of the cytokine interferon-inducible protein 10, which arises from the TRIF-dependent pathway. The latter pathway was somewhat more potently inhibited than the MyD88-dependent pathway. Furthermore, it was observed that the natural LPS possesses much greater activity than the synthetic and isolated lipid As, which indicates that di-KDO moiety is important for optimal biological activity. It has also been found that isolated R.sin-1 LPS and lipid A agonize a mouse macrophage cell line to induce the production of TNF-α and interferon beta in a Toll-like receptor 4-dependent manner demonstrating species specific properties.

  根瘤菌素-1（R.sin-1）中的 LPS 可拮抗大肠杆菌 LPS 在人类单核细胞中产生的肿瘤坏死因子α（TNF-α）。因此，这些化合物为开发预防或治疗脓毒性休克的疗法提供了有趣的线索。然而，由于这些化合物容易发生 β-消除反应，生成无生物活性的烯酮衍生物，因此阻碍了详细的结构活性关系研究。为了解决这个问题，我们以聚合的方式化学合成了一种 R.sin-1 脂质 A 衍生物，其中近端糖单元 C-3 上的β-羟基酯被一个醚连接分子取代。不出所料，这种衍生物的化学稳定性大大提高。此外，它拮抗肠道 LPS 诱导的 TNF-α 生成的能力仅略低于母体酯修饰衍生物，这表明醚键脂质对生物活性的影响微乎其微。此外，研究首次表明，R.sin-1 LPS 和经醚修饰的脂质 A 还能拮抗细胞因子干扰素诱导蛋白 10 的产生，而干扰素诱导蛋白 10 是由 TRIF 依赖性途径产生的。与依赖 MyD88 的途径相比，后者的抑制作用更强。此外，还观察到天然 LPS 的活性远高于合成和分离脂质 As，这表明二 KDO 分子对最佳生物活性非常重要。研究还发现，分离出的 R.sin-1 LPS 和脂质 A 可激动小鼠巨噬细胞系，以 Toll 样受体 4 依赖性方式诱导 TNF-α 和干扰素 beta 的产生，这表明了物种特异性。