bis(amino-Nε-tert-butyloxycarbonyl-(S)-lysinyl)-4,7,10-trioxa-1,13-tridecandiamine | 1282035-01-1

• 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: bis(amino-Nε-tert-butyloxycarbonyl-(S)-lysinyl)-4,7,10-trioxa-1,13-tridecandiamine
• CAS: 1282035-01-1
• 化学式: C₃₂H₆₄N₆O₉
• 分子量: 676.895
• InChiKey: SCJFCBHIPVUGAH-UIOOFZCWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.09
• 重原子数：
  47.0
• 可旋转键数：
  26.0
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.88
• 拓扑面积：
  214.59
• 氢给体数：
  6.0
• 氢受体数：
  11.0

反应信息

• 作为反应物：
  描述：

  bis(amino-Nε-tert-butyloxycarbonyl-(S)-lysinyl)-4,7,10-trioxa-1,13-tridecandiamine 、 1-(4-methoxybenzyl)-3-(1-(4-methoxybenzyl)-3-(1-(4-methoxybenzyl)-3-nitro-1H-pyrazole-5-carboxamido)-1H-pyrazole-5-carboxamido)-1H-pyrazole-5-carboxylic acid 在 N-甲基吗啉 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 作用下， 以 二氯甲烷 为溶剂， 反应 96.0h， 以52%的产率得到tert-butyl (10S,28S)-10,28-bis(1-(4-methoxybenzyl)-3-(1-(4-methoxybenzyl)-3-(1-(4-methoxybenzyl)-3-nitro-1H-pyrazole-5-carboxamido)-1H-pyrazole-5-carboxamido)-1H-pyrazole-5-carboxamido)-2,2-dimethyl-4,11,27-trioxo-16,19,22-trioxa-5,12,26-triazadotriacontan-32-ylcarbamate
  参考文献：
  名称：

  [EN] NEW COMPOUNDS FOR THE TREATMENT OF DISEASES RELATED TO PROTEIN MISFOLDING
  [FR] NOUVEAUX COMPOSÉS POUR LE TRAITEMENT DE MALADIES LIÉES À UN MAUVAIS REPLIEMENT DE PROTÉINES

  摘要：

  本发明涉及蛋白质错折疾病领域，因此涉及与异常或致病性蛋白质和/或肽的三维折叠相关或诱导的疾病，或与致病性蛋白质和/或肽的构象变化相关的疾病，如阿尔茨海默病。具体地，本发明提供了新型三聚吡唑化合物，这些化合物在治疗上述蛋白质错折疾病方面表现出治疗有效性，并涉及其用于治疗此类蛋白质错折疾病，特别是神经退行性疾病，以及包含这些化合物的药物或制剂组合物。

  公开号：

  WO2011050864A1
• 作为产物：
  描述：

  Bis(N-benzyloxycarbonyl-Nε-tert-butyloxycarbonyl-(S)-lysinyl)-4,7,10-trioxa-1,13-tridecanediamine 在 palladium 10% on activated carbon 氢气 作用下， 以 四氢呋喃 为溶剂， 以96%的产率得到bis(amino-Nε-tert-butyloxycarbonyl-(S)-lysinyl)-4,7,10-trioxa-1,13-tridecandiamine
  参考文献：
  名称：

  [EN] NEW COMPOUNDS FOR THE TREATMENT OF DISEASES RELATED TO PROTEIN MISFOLDING
  [FR] NOUVEAUX COMPOSÉS POUR LE TRAITEMENT DE MALADIES LIÉES À UN MAUVAIS REPLIEMENT DE PROTÉINES

  摘要：

  本发明涉及蛋白质错折疾病领域，因此涉及与异常或致病性蛋白质和/或肽的三维折叠相关或诱导的疾病，或与致病性蛋白质和/或肽的构象变化相关的疾病，如阿尔茨海默病。具体地，本发明提供了新型三聚吡唑化合物，这些化合物在治疗上述蛋白质错折疾病方面表现出治疗有效性，并涉及其用于治疗此类蛋白质错折疾病，特别是神经退行性疾病，以及包含这些化合物的药物或制剂组合物。

  公开号：

  WO2011050864A1

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.