N-(1-cyclohexylethyl)-3-(3-(3-nitro-1H-pyrazole-5-carboxamido)-1H-pyrazole-5-carboxamido)-1H-pyrazole-5-carboxamide | 1282034-78-9

• 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: N-(1-cyclohexylethyl)-3-(3-(3-nitro-1H-pyrazole-5-carboxamido)-1H-pyrazole-5-carboxamido)-1H-pyrazole-5-carboxamide
• 英文别名: N-[(1R)-1-cyclohexylethyl]-3-[[3-[(5-nitro-1H-pyrazole-3-carbonyl)amino]-1H-pyrazole-5-carbonyl]amino]-1H-pyrazole-5-carboxamide
• CAS: 1282034-78-9
• 化学式: C₂₀H₂₄N₁₀O₅
• 分子量: 484.475
• InChiKey: XQFFYSCKVYYOEK-SNVBAGLBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  35
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  219
• 氢给体数：
  6
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  N-(1-cyclohexylethyl)-1-(4-methoxybenzyl)-3-(1-(4-methoxybenzyl)-3-(1-(4-methoxybenzyl)-3-nitro-1H-pyrazole-5-carboxamido)-1H-pyrazole-5-carboxamido)-1H-pyrazole-5-carboxamide 在 三氟乙酸 作用下， 反应 5.0h， 以82%的产率得到N-(1-cyclohexylethyl)-3-(3-(3-nitro-1H-pyrazole-5-carboxamido)-1H-pyrazole-5-carboxamido)-1H-pyrazole-5-carboxamide
  参考文献：
  名称：

  Rational Design of β-Sheet Ligands Against Aβ₄₂-Induced Toxicity

  摘要：

  A beta-sheet-binding scaffold was equipped with long-range chemical groups for tertiary contacts toward specific regions of the Alzheimer's A beta fibril. The new constructs contain a trimeric aminopyrazole carboxylic acid, elongated with a C-terminal binding site, whose influence on the aggregation behavior of the A beta(42) peptide was studied. MD simulations after trimer docking to the anchor point (F19/F20) suggest distinct groups of complex structures each of which featured additional specific interactions with characteristic A beta regions. Members of each group also displayed a characteristic pattern in their antiaggregational behavior toward A beta. Specifically, remote lipophilic moieties such as a dodecyl, cyclohexyl, or LPFFD fragment can form dispersive interactions with the nonpolar cluster of amino acids between I31 and V36. They were shown to strongly reduce Thioflavine T (ThT) fluorescence and protect cells from A beta lesions (MTT viability assays). Surprisingly, very thick fibrils and a high beta-sheet content were detected in transmission electron microscopy (TEM) and CD spectroscopic experiments. On the other hand, distant single or multiple lysines which interact with the ladder of stacked E22 residues found in A beta fibrils completely dissolve existing beta-sheets (ThT, CD) and lead to unstructured, nontoxic material (TEM, MTT). Finally, the triethyleneglycol spacer between heterocyclic beta-sheet ligand and appendix was found to play an active role in destabilizing the turn of the U-shaped protofilament. Fluorescence correlation spectroscopy (FCS) and sedimentation velocity analysis (SVA) provided experimental evidence for some smaller benign aggregates of very thin, delicate structure (TEM, MTT). A detailed investigation by dynamic light scattering (DLS) and other methods proved that none of the new ligands acts as a colloid. The evolving picture for the disaggregation mechanism by these new hybrid ligands implies transformation of well-ordered fibrils into less structured aggregates with a high molecular weight. In the few cases where fibrillar components remain, these display a significantly altered morphology and have lost their acute cellular toxicity.

  DOI：

  10.1021/ja107675n

文献信息

• Rational Design of β-Sheet Ligands Against Aβ₄₂-Induced Toxicity
  作者：Katrin Hochdörffer、Julia März-Berberich、Luitgard Nagel-Steger、Matthias Epple、Wolfgang Meyer-Zaika、Anselm H.C. Horn、Heinrich Sticht、Sharmistha Sinha、Gal Bitan、Thomas Schrader

  DOI：10.1021/ja107675n

  日期：2011.3.30

  A beta-sheet-binding scaffold was equipped with long-range chemical groups for tertiary contacts toward specific regions of the Alzheimer's A beta fibril. The new constructs contain a trimeric aminopyrazole carboxylic acid, elongated with a C-terminal binding site, whose influence on the aggregation behavior of the A beta(42) peptide was studied. MD simulations after trimer docking to the anchor point (F19/F20) suggest distinct groups of complex structures each of which featured additional specific interactions with characteristic A beta regions. Members of each group also displayed a characteristic pattern in their antiaggregational behavior toward A beta. Specifically, remote lipophilic moieties such as a dodecyl, cyclohexyl, or LPFFD fragment can form dispersive interactions with the nonpolar cluster of amino acids between I31 and V36. They were shown to strongly reduce Thioflavine T (ThT) fluorescence and protect cells from A beta lesions (MTT viability assays). Surprisingly, very thick fibrils and a high beta-sheet content were detected in transmission electron microscopy (TEM) and CD spectroscopic experiments. On the other hand, distant single or multiple lysines which interact with the ladder of stacked E22 residues found in A beta fibrils completely dissolve existing beta-sheets (ThT, CD) and lead to unstructured, nontoxic material (TEM, MTT). Finally, the triethyleneglycol spacer between heterocyclic beta-sheet ligand and appendix was found to play an active role in destabilizing the turn of the U-shaped protofilament. Fluorescence correlation spectroscopy (FCS) and sedimentation velocity analysis (SVA) provided experimental evidence for some smaller benign aggregates of very thin, delicate structure (TEM, MTT). A detailed investigation by dynamic light scattering (DLS) and other methods proved that none of the new ligands acts as a colloid. The evolving picture for the disaggregation mechanism by these new hybrid ligands implies transformation of well-ordered fibrils into less structured aggregates with a high molecular weight. In the few cases where fibrillar components remain, these display a significantly altered morphology and have lost their acute cellular toxicity.