D-3-O-allyl-1,4,5,6-tetra-O-benzyl-2-O-butyl-myo-inositol | 205247-02-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: D-3-O-allyl-1,4,5,6-tetra-O-benzyl-2-O-butyl-myo-inositol
• 英文别名: D-1-O-Allyl-3,4,5,6-tetra-O-benzyl-2-O-butyl-myo-inositol；[(1R,2R,3S,4R,5S,6S)-2-butoxy-4,5,6-tris(phenylmethoxy)-3-prop-2-enoxycyclohexyl]oxymethylbenzene
• CAS: 205247-02-5
• 化学式: C₄₁H₄₈O₆
• 分子量: 636.829
• InChiKey: SHKSKSNJDYHNCS-LYVVXKSESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.4
• 重原子数：
  47
• 可旋转键数：
  19
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  55.4
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  D-3-O-allyl-1,4,5,6-tetra-O-benzyl-2-O-butyl-myo-inositol 在 Wilkinson's catalyst 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 乙醇 为溶剂， 生成 D-1,4,5,6-tetra-O-benzyl-2-O-butyl-myo-inositol
  参考文献：
  名称：

  Antagonists of myo-inositol 3,4,5,6-tetrakisphosphate allow repeated epithelial chloride secretion

  摘要：

  Cystic fibrosis (CF) patients suffer from a defect in hydration of mucosal membranes due to mutations in the cystic fibrosis transmembrane regulator (CFTR), an apical chloride channel in mucosal epithelia. Disease expression in CF knockout mice is organ specific, varying with the level of expression of calcium activated Cl- channels (CLCA). Therefore, restoring transepithelial Cl- secretion by augmenting alternate Cl- channels, such as CLCA, could be beneficial. However, CLCA-mediated Cl- secretion is transient, due in part to the inhibitory effects of myo-inositol 3,4,5,6-tetrakisphosphate [Ins(3,4,5,6)P-4]. This suggests that antagonists of Ins(3,4,5,6)P-4 could be useful in treatment of CF. We have, therefore, synthesized a series of membrane-permeant Ins(3,4,5,6)P-4 derivatives, carrying alkyl substituents on the hydroxyl groups and screened them for effects on Cl- secretion in a human colonic epithelial cell line, T-84, While membrane-permeant Ins(3,4,5,6)P-4 derivatives had no direct effects on carbachol-stimulated Cl- secretion, Ins(3,4,5,6)P-4 derivatives, but not enantiomeric Ins(1,4,5,6)P-4 derivatives, reversed the inhibitory effect of Ins(3,4,5,6)P-4 on subsequent thapsigargin activation of Cl- secretion. The extent of the antagonistic effect of the Ins(3,4,5,6)P-4 derivatives varied with the position of the alkyl substituents. Derivatives with a cyclohexylidene ketal or a butyl-chain at the 1-position reversed the Ins(3,4,5,6)P-4-mediated inhibition of Cl- secretion by up to 96 and 85%, respectively, whereas butylation of the 1- and 2-position generated a reversal effect of only 65%. Derivatives carrying the butyl chain only at the 2-position showed no antagonistic effect. These data: (1) Support the hypothesis that Ins(3,4,5,6)P-4 stereospecifically inhibits Ca2+ activated Cl- secretion and that Ins(3,4,5,6)P-4 mediates most, if not all of the cholinergic-mediated inhibition of chloride secretion in T84 cells; (2) Demonstrate Ins(3,4,5,6)P-4-mediated inhibition can be completely reversed with rationally designed membrane-permeant Ins(3,4,5,6)P4 antagonists; (3) Demonstrate that a SAR for membrane-permeant Ins(3,4,5,6) P-4 antagonists can be generated and screened in a physiologically relevant cell-based assay; (4) Indicate that Ins(3,4,5,6)P-4 derivatives could serve as a starting point for the development of therapeutics to treat cystic fibrosis. (C) 2003 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(03)00188-3
• 作为产物：
  描述：

  1,4,5,6-tetra-O-benzyl-myo-inositol 在 sodium hydride 、 二正丁基氧化锡 作用下， 以 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 20.0h， 生成 D-3-O-allyl-1,4,5,6-tetra-O-benzyl-2-O-butyl-myo-inositol
  参考文献：
  名称：

  Antagonists of myo-inositol 3,4,5,6-tetrakisphosphate allow repeated epithelial chloride secretion

  摘要：

  Cystic fibrosis (CF) patients suffer from a defect in hydration of mucosal membranes due to mutations in the cystic fibrosis transmembrane regulator (CFTR), an apical chloride channel in mucosal epithelia. Disease expression in CF knockout mice is organ specific, varying with the level of expression of calcium activated Cl- channels (CLCA). Therefore, restoring transepithelial Cl- secretion by augmenting alternate Cl- channels, such as CLCA, could be beneficial. However, CLCA-mediated Cl- secretion is transient, due in part to the inhibitory effects of myo-inositol 3,4,5,6-tetrakisphosphate [Ins(3,4,5,6)P-4]. This suggests that antagonists of Ins(3,4,5,6)P-4 could be useful in treatment of CF. We have, therefore, synthesized a series of membrane-permeant Ins(3,4,5,6)P-4 derivatives, carrying alkyl substituents on the hydroxyl groups and screened them for effects on Cl- secretion in a human colonic epithelial cell line, T-84, While membrane-permeant Ins(3,4,5,6)P-4 derivatives had no direct effects on carbachol-stimulated Cl- secretion, Ins(3,4,5,6)P-4 derivatives, but not enantiomeric Ins(1,4,5,6)P-4 derivatives, reversed the inhibitory effect of Ins(3,4,5,6)P-4 on subsequent thapsigargin activation of Cl- secretion. The extent of the antagonistic effect of the Ins(3,4,5,6)P-4 derivatives varied with the position of the alkyl substituents. Derivatives with a cyclohexylidene ketal or a butyl-chain at the 1-position reversed the Ins(3,4,5,6)P-4-mediated inhibition of Cl- secretion by up to 96 and 85%, respectively, whereas butylation of the 1- and 2-position generated a reversal effect of only 65%. Derivatives carrying the butyl chain only at the 2-position showed no antagonistic effect. These data: (1) Support the hypothesis that Ins(3,4,5,6)P-4 stereospecifically inhibits Ca2+ activated Cl- secretion and that Ins(3,4,5,6)P-4 mediates most, if not all of the cholinergic-mediated inhibition of chloride secretion in T84 cells; (2) Demonstrate Ins(3,4,5,6)P-4-mediated inhibition can be completely reversed with rationally designed membrane-permeant Ins(3,4,5,6)P4 antagonists; (3) Demonstrate that a SAR for membrane-permeant Ins(3,4,5,6) P-4 antagonists can be generated and screened in a physiologically relevant cell-based assay; (4) Indicate that Ins(3,4,5,6)P-4 derivatives could serve as a starting point for the development of therapeutics to treat cystic fibrosis. (C) 2003 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(03)00188-3

文献信息

• Inositol polyphosphates and methods of using same
  申请人：The Regents of the University of California

  公开号：US05880099A1

  公开（公告）日：1999-03-09

  The present invention provides compositions that are cell permeable antagonists of inositol polyphosphates. In addition, the invention provides methods for enhancing chloride ion secretion from a cell by contacting the cells with cell permeable antagonists of inositol polyphosphates. The invention also provides methods for enhancing chloride ion secretion in an individual by administering cell permeable antagonists of inositol polyphosphates to the individual. The invention additionally provides methods for alleviating a sign or symptom associated with cystic fibrosis in an individual by administering a cell permeable antagonist of inositol polyphosphates to the individual. The invention also provides compositions that are cell permeable agonists of inositol polyphosphates. In addition, the invention provides methods for decreasing chloride ion secretion from a cell by contacting the cell with cell permeable agonists of inositol polyphosphates. The invention also provides methods for decreasing chloride ion secretion in an individual by administering cell permeable agonists of inositol polyphosphates to the individual. The invention additionally provides methods for alleviating a sign or symptom associated with secretory diarrhea in an individual by administering cell permeable agonists of inositol polyphosphates to the individual.

  本发明提供了一种可透过细胞的肌醇多磷酸拮抗剂。此外，本发明还提供了一种通过将细胞与肌醇多磷酸的细胞可透过拮抗剂接触来增强细胞分泌氯离子的方法。本发明还提供了一种通过向个体施用肌醇多磷酸的细胞可透过拮抗剂来增强个体中氯离子分泌的方法。本发明还进一步提供了一种通过向个体施用肌醇多磷酸的细胞可透过拮抗剂来缓解与囊性纤维化相关的体征或症状的方法。本发明还提供了一种肌醇多磷酸的细胞可透过激动剂。此外，本发明还提供了一种通过将细胞与肌醇多磷酸的细胞可透过激动剂接触来减少细胞分泌氯离子的方法。本发明还提供了一种通过向个体施用肌醇多磷酸的细胞可透过激动剂来减少个体中氯离子分泌的方法。本发明还进一步提供了一种通过向个体施用肌醇多磷酸的细胞可透过激动剂来缓解与分泌性腹泻相关的体征或症状的方法。
• US5880099A
  申请人：——

  公开号：US5880099A

  公开（公告）日：1999-03-09
• US5977078A
  申请人：——

  公开号：US5977078A

  公开（公告）日：1999-11-02