7-<<(benzyloxy)carbonyl>amino>-4-chloro-3-methoxyisocoumarin | 138695-81-5

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 异香豆素及其衍生物
• 英文名称: 7-<<(benzyloxy)carbonyl>amino>-4-chloro-3-methoxyisocoumarin
• 英文别名: 7-benzyloxycarbonylamino-4-chloro-3-methoxyisocoumarin；benzyl N-(4-chloro-3-methoxy-1-oxoisochromen-7-yl)carbamate
• CAS: 138695-81-5
• 化学式: C₁₈H₁₄ClNO₅
• 分子量: 359.766
• InChiKey: VMVQEDRUPKEFGF-UHFFFAOYSA-N

物化性质

• 沸点：
  514.9±50.0 °C(Predicted)
• 密度：
  1.42±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  73.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  7-氨基-4-氯-3-甲氧基异香豆素 在 碳酸氢钠 作用下， 以 四氢呋喃 为溶剂， 生成 7-<<(benzyloxy)carbonyl>amino>-4-chloro-3-methoxyisocoumarin
  参考文献：
  名称：

  Further characterization of a putative serine protease contributing to the γ-secretase cleavage of β-amyloid precursor protein

  摘要：

  The 3-alkoxy-7-amino-4-chloro-isocoumarins JLK-6 and JLK-2 have been shown to markedly reduce the production of Amyloid beta-peptide (A beta) by Amyloid-beta Precursor Protein (APP) expressing HEK293 cells by affecting the gamma-secretase cleavage of APP, with no effect on the cleavage of the Notch receptor. This suggested that these compounds do not directly inhibit the presenilin-dependent gamma-secretase complex but more likely interfere with an upstream target involved in gamma-secretase-associated pathway. The mechanism of action of these compounds is unknown and there are high fundamental and therapeutical interests to unravel their target. Isocoumarin compounds were previously shown to behave as potent mechanism-based irreversible inhibitors of serine proteases, suggesting that the JLK-directed target could belong to such enzyme family. To get further insight into structure-activity relationships and to develop more potent isocoumarin derivatives, we have synthesized and evaluated a series of isocoumarin analogues with modifications at positions 3, 4 and 7. In particular, the 7-amino group was substituted with either acyl, urethane, alkyl or aryl groups, which could represent additional interaction sites. Altogether, the results highlighted the essential integrity of the 3-alkoxy-7-amino-4-chloro-isocoumarin scaffold for A beta-lowering activity and supported the involvement of a seri ne protease, or may be more generally, a serine hydrolase. The newly reported 7-N-alkyl series produced the most active compounds with an IC50 between 10 and 30 mu M. Finally, we also explored peptide boronates, a series of reversible serine protease inhibitors, previously shown to also lower cellular A beta production. The presented data suggested they could act on the same target or interfere with the same pathway as isocoumarins derivatives. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.11.045

文献信息

• Effect of the 7-amino substituent on the inhibitory potency of mechanism-based isocoumarin inhibitors for porcine pancreatic and human neutrophil elastases: a 1.85-.ANG. x-ray structure of the complex between porcine pancreatic elastase and 7-[(N-tosylphenylalanyl)amino]-4-chloro-3-methoxyisocoumarin
  作者：Maria A. Hernandez、James C. Powers、Jan Glinski、Jozef Oleksyszyn、J. Vijayalakshmi、Edgar F. Meyer

  DOI：10.1021/jm00084a018

  日期：1992.3

  A series of new acyl, urea, and carbonate derivatives of 7-amino-4-chloro-3-methoxyisocoumarin were synthesized and evaluated as irreversible inhibitors of human neutrophil elastase (HNE) and porcine pancreatic elastase (PPE). Inhibition of HNE is directly related to the hydrophobicity of the substituent on the 7-amino group. The N-Tos-Phe derivative (19) is the best HNE inhibitor with a second-order

  合成了一系列新的7-氨基-4-氯-3-甲氧基异香豆素的酰基，脲和碳酸酯衍生物，并作为人嗜中性弹性蛋白酶（HNE）和猪胰弹性蛋白酶（PPE）的不可逆抑制剂进行了评估。HNE的抑制与7-氨基上取代基的疏水性直接相关。N-Tos-Phe衍生物（19）是最好的HNE抑制剂，其二级速率常数kobs / [I] = 200,000 M-1 s-1。该系列中最接近的类似物3,3-二苯基丙酰基衍生物5具有HNE的kobs / [I] = 130,000 M-1 s-1。与Tos-Phe衍生物19相比，苯乙酰基衍生物2和碳酸盐22和25提供了极其稳定的酶-抑制剂复合物，两种弹性蛋白酶的脱酰化半衰期均长于48小时。N-苯基脲衍生物25是PPE的最佳抑制剂，其二级速率常数kobs / [I] = 7300 M-1 s-1。以1.85-A的分辨率测定了PPE与N-甲苯磺酰基-Phe衍生物19的配合物的晶体结构，并将其精制为最终的R因子为16
• US5089633A
  申请人：——

  公开号：US5089633A

  公开（公告）日：1992-02-18
• US5324648A
  申请人：——

  公开号：US5324648A

  公开（公告）日：1994-06-28