methyl (2S)-4-methyl-2-[[(2S)-3-methyl-2-[3-[[(2R,3S,4S,5R,6R)-3,4,5-trihydroxy-6-[2-[[(2S)-3-methyl-2-[[(2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]amino]butanoyl]amino]ethoxy]oxan-2-yl]methoxy]propanoylamino]butanoyl]amino]pentanoate | 1351945-76-0

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: methyl (2S)-4-methyl-2-[[(2S)-3-methyl-2-[3-[[(2R,3S,4S,5R,6R)-3,4,5-trihydroxy-6-[2-[[(2S)-3-methyl-2-[[(2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]amino]butanoyl]amino]ethoxy]oxan-2-yl]methoxy]propanoylamino]butanoyl]amino]pentanoate
• CAS: 1351945-76-0
• 化学式: C₃₆H₆₅N₅O₁₄
• 分子量: 791.937
• InChiKey: DIVVWVXKDQTUNK-UEBPAERWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  55
• 可旋转键数：
  24
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.83
• 拓扑面积：
  269
• 氢给体数：
  8
• 氢受体数：
  14

反应信息

• 作为反应物：
  描述：

  methyl (2S)-4-methyl-2-[[(2S)-3-methyl-2-[3-[[(2R,3S,4S,5R,6R)-3,4,5-trihydroxy-6-[2-[[(2S)-3-methyl-2-[[(2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]amino]butanoyl]amino]ethoxy]oxan-2-yl]methoxy]propanoylamino]butanoyl]amino]pentanoate 、 三氟乙酸 以 二氯甲烷 为溶剂， 以100%的产率得到methyl (2S)-2-[[(2S)-2-[3-[[(2R,3S,4S,5R,6R)-6-[2-[[(2S)-2-[[(2S)-2-aminopropanoyl]amino]-3-methylbutanoyl]amino]ethoxy]-3,4,5-trihydroxyoxan-2-yl]methoxy]propanoylamino]-3-methylbutanoyl]amino]-4-methylpentanoate;2,2,2-trifluoroacetic acid
  参考文献：
  名称：

  Structure–activity relationships of sugar-based peptidomimetics as modulators of amyloid β-peptide early oligomerization and fibrillization

  摘要：

  Alzheimer's disease is a neurodegenerative disorder linked to oligomerization and fibrillization of amyloid beta peptides. A beta(1-42) being the most aggregative and neurotoxic amyloid peptide, we report herein the capacity of sugar-based pentapeptide analogs to modulate the A beta(1-42) aggregation process using thioflavin fluorescence and transmission electron microscopy assays. The importance of the free hydroxyl groups of the sugar moiety, used as a beta-breaker element, is confirmed since hydroxylated compounds inhibit the aggregation process while benzylated ones enhance it. Furthermore, the most effective molecules were also evaluated by a recently developed capillary electrophoresis method, providing in vitro monitoring of the crucial, very early stages of the self-assembly process. This technique allowed us to investigate the effect of these compounds on the small non-fibrillar A beta(1-42) oligomers suspected by several groups worldwide as highly neurotoxic. We clearly demonstrated that molecules delaying the aggregation can stabilize the monomeric peptide or promote the formation of soluble oligomeric species. In contrast, molecules that accelerate the aggregation can prevent the presence of small toxic oligomers. (c) 2014 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2014.09.031
• 作为产物：
  描述：

  methyl (3-(((2R,3R,4S,5R)-6-(2-aminoethoxy)-3,4,5-tris(benzyloxy)tetrahydro-2H-pyran-2-yl)methoxy)propanoyl)-L-valyl-L-leucinate 在 氢气 、 palladium(II) hydroxide 、 1-羟基苯并三唑 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 94.0h， 生成 methyl (2S)-4-methyl-2-[[(2S)-3-methyl-2-[3-[[(2R,3S,4S,5R,6R)-3,4,5-trihydroxy-6-[2-[[(2S)-3-methyl-2-[[(2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]amino]butanoyl]amino]ethoxy]oxan-2-yl]methoxy]propanoylamino]butanoyl]amino]pentanoate
  参考文献：
  名称：

  Sugar-based peptidomimetics inhibit amyloid β-peptide aggregation

  摘要：

  Alzheimer's disease is characterized by the oligomerization and amyloid fibril formation of amyloid beta-peptide (A beta). We describe a novel class of small water-soluble A beta binding peptidomimetics based on two hydrophobic Ala-Val and Val-Leu dipeptides linked to a D-glucopyranosyl scaffold through aminoalkyl and carboxyethyl links in C1 and C6 positions. These compounds combine the targeting of hydrophobic recognition interfaces with an original hydrophilic sugar beta-breakage strategy. These molecules were shown, by fluorescence thioflavin-T assays, to dramatically slow down the kinetics of amyloid fibril formation even at a low peptidomimetics to A beta ratio of 0.1:1. Electron microscopy images revealed that the peptidomimetics efficiently reduced the amount of typical amyloid fibrils. NMR saturation transfer difference experiments indicated that these molecules interact with A beta aggregated species through their hydrophobic amino acid residues. This inhibition effect was found to be sequence-specific since these molecules did not alter the kinetics of aggregation of another amyloid peptide, IAPP, involved in type 2 diabetes mellitus. (C) 2011 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2011.10.008

文献信息

• Sugar-based peptidomimetics inhibit amyloid β-peptide aggregation
  作者：Bertrand Dorgeret、Lucie Khemtémourian、Isabelle Correia、Jean-Louis Soulier、Olivier Lequin、Sandrine Ongeri

  DOI：10.1016/j.ejmech.2011.10.008

  日期：2011.12

  Alzheimer's disease is characterized by the oligomerization and amyloid fibril formation of amyloid beta-peptide (A beta). We describe a novel class of small water-soluble A beta binding peptidomimetics based on two hydrophobic Ala-Val and Val-Leu dipeptides linked to a D-glucopyranosyl scaffold through aminoalkyl and carboxyethyl links in C1 and C6 positions. These compounds combine the targeting of hydrophobic recognition interfaces with an original hydrophilic sugar beta-breakage strategy. These molecules were shown, by fluorescence thioflavin-T assays, to dramatically slow down the kinetics of amyloid fibril formation even at a low peptidomimetics to A beta ratio of 0.1:1. Electron microscopy images revealed that the peptidomimetics efficiently reduced the amount of typical amyloid fibrils. NMR saturation transfer difference experiments indicated that these molecules interact with A beta aggregated species through their hydrophobic amino acid residues. This inhibition effect was found to be sequence-specific since these molecules did not alter the kinetics of aggregation of another amyloid peptide, IAPP, involved in type 2 diabetes mellitus. (C) 2011 Elsevier Masson SAS. All rights reserved.
• Structure–activity relationships of sugar-based peptidomimetics as modulators of amyloid β-peptide early oligomerization and fibrillization
  作者：Julia Kaffy、Dimitri Brinet、Jean-Louis Soulier、Lucie Khemtémourian、Olivier Lequin、Myriam Taverna、Benoît Crousse、Sandrine Ongeri

  DOI：10.1016/j.ejmech.2014.09.031

  日期：2014.10

  Alzheimer's disease is a neurodegenerative disorder linked to oligomerization and fibrillization of amyloid beta peptides. A beta(1-42) being the most aggregative and neurotoxic amyloid peptide, we report herein the capacity of sugar-based pentapeptide analogs to modulate the A beta(1-42) aggregation process using thioflavin fluorescence and transmission electron microscopy assays. The importance of the free hydroxyl groups of the sugar moiety, used as a beta-breaker element, is confirmed since hydroxylated compounds inhibit the aggregation process while benzylated ones enhance it. Furthermore, the most effective molecules were also evaluated by a recently developed capillary electrophoresis method, providing in vitro monitoring of the crucial, very early stages of the self-assembly process. This technique allowed us to investigate the effect of these compounds on the small non-fibrillar A beta(1-42) oligomers suspected by several groups worldwide as highly neurotoxic. We clearly demonstrated that molecules delaying the aggregation can stabilize the monomeric peptide or promote the formation of soluble oligomeric species. In contrast, molecules that accelerate the aggregation can prevent the presence of small toxic oligomers. (c) 2014 Elsevier Masson SAS. All rights reserved.