2-(2-methoxy-2-oxoethyl)-5-nitrobenzoic acid | 62252-24-8

• 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: 2-(2-methoxy-2-oxoethyl)-5-nitrobenzoic acid
• CAS: 62252-24-8
• 化学式: C₁₀H₉NO₆
• 分子量: 239.185
• InChiKey: SOEHEDZSEMCWQE-UHFFFAOYSA-N

物化性质

• 熔点：
  158 °C
• 沸点：
  407.3±35.0 °C(Predicted)
• 密度：
  1.435±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  17
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  109
• 氢给体数：
  1
• 氢受体数：
  6

安全信息

• 危险性防范说明：
  P261,P280,P301+P312,P302+P352,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

反应信息

• 作为反应物：
  描述：

  2-(2-methoxy-2-oxoethyl)-5-nitrobenzoic acid 在 palladium on activated charcoal 五氯化磷 、 氢气 作用下， 以 四氢呋喃 、 甲苯 为溶剂， 反应 21.0h， 生成 7-氨基-4-氯-3-甲氧基异香豆素
  参考文献：
  名称：

  Synthesis of new 3-alkoxy-7-amino-4-chloro-isocoumarin derivatives as new β-amyloid peptide production inhibitors and their activities on various classes of protease

  摘要：

  A series of new 7-substituted-4-chloro-3-alkoxy isocoumarin derivatives were synthesized and evaluated as inhibitors of representative classes of proteases: serine protease (alpha-chymotrypsin, trypsin), cysteine protease (Caspase-3), and aspartyl protease (HIV-protease), 20S proteasome and also as inhibitors of amyloid peptide gamma-secretase-mediated production. Protease inhibition selectivity is directly related to the structure of the substituent at the 7-position of the isocoumarin nucleus. 7-Nitro-isocoumarin derivatives (4c, 4d 4f) are potent alpha-chymotrypsin inhibitors but slightly active or inactive on HIV-protease, as well as on cysteine protease. In contrast.. only derivatives bearing a free amino (5d, 5f) or a substituted amino group (6f) at the 7-position of the isocoumarin nucleus, were found weakly active or inactive on alpha-chymotrypsin, trypsin, Caspase-3 and HIV-protease, but prevent gamma-secretase-mediated production of Abeta 40/42 amyloid peptides, which is known to be involved in Alzheimer's disease. Moreover, the most active compounds on beta-amyloid peptide production [JLK6 (5d), JLK2 (5f) and JLK7 (6f)] show only weak or moderate inhibitory activity on the 20S proteasome. The obtained results suggest that the described new isocoumarin analogues could be of interest, since compounds like JLK6 (5d), JLK2 (5f) and JLK7 (6f) can be considered as possible hits for the development of new agents directed towards Alzheimer's disease. (C) 2003 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(03)00235-9
• 作为产物：
  描述：

  邻羧基苯乙酸 在 硫酸 、 硝酸 作用下， 反应 6.12h， 生成 2-(2-methoxy-2-oxoethyl)-5-nitrobenzoic acid
  参考文献：
  名称：

  Synthesis of new 3-alkoxy-7-amino-4-chloro-isocoumarin derivatives as new β-amyloid peptide production inhibitors and their activities on various classes of protease

  摘要：

  A series of new 7-substituted-4-chloro-3-alkoxy isocoumarin derivatives were synthesized and evaluated as inhibitors of representative classes of proteases: serine protease (alpha-chymotrypsin, trypsin), cysteine protease (Caspase-3), and aspartyl protease (HIV-protease), 20S proteasome and also as inhibitors of amyloid peptide gamma-secretase-mediated production. Protease inhibition selectivity is directly related to the structure of the substituent at the 7-position of the isocoumarin nucleus. 7-Nitro-isocoumarin derivatives (4c, 4d 4f) are potent alpha-chymotrypsin inhibitors but slightly active or inactive on HIV-protease, as well as on cysteine protease. In contrast.. only derivatives bearing a free amino (5d, 5f) or a substituted amino group (6f) at the 7-position of the isocoumarin nucleus, were found weakly active or inactive on alpha-chymotrypsin, trypsin, Caspase-3 and HIV-protease, but prevent gamma-secretase-mediated production of Abeta 40/42 amyloid peptides, which is known to be involved in Alzheimer's disease. Moreover, the most active compounds on beta-amyloid peptide production [JLK6 (5d), JLK2 (5f) and JLK7 (6f)] show only weak or moderate inhibitory activity on the 20S proteasome. The obtained results suggest that the described new isocoumarin analogues could be of interest, since compounds like JLK6 (5d), JLK2 (5f) and JLK7 (6f) can be considered as possible hits for the development of new agents directed towards Alzheimer's disease. (C) 2003 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(03)00235-9

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
• Alkyne derivatives of isocoumarins as clickable activity-based probes for serine proteases
  作者：Ute Haedke、Markus Götz、Philipp Baer、Steven H.L. Verhelst

  DOI：10.1016/j.bmc.2011.03.014

  日期：2012.1

  detect their target proteases in a proteome background in a sensitive manner (down to 0.007% of total protein). Furthermore, we show activity-dependent and selective labeling of endogenous proteases in a tissue proteome. These ICs therefore represent a valuable extension to already existing ABPs for serine proteases and may be instrumental in future elucidation of serine protease functions.

  基于活动的探针（ABP）已发现在功能蛋白质组学研究中的使用越来越多。近来，可与点击化学结合使用的ABP由于其在体内和体外的灵活应用而受到了特别的关注。此外，持续需要针对小部分酶的新ABP。我们在此报告基于4-氯-异香豆素（IC）亲电子体的新型可点击ABP，这是一种基于机理的抑制剂骨架，与丝氨酸蛋白酶共价结合。我们描述了一个IC ABPs小库的合成，该库包含炔烃功能和一组不同的选择性元素。IC结构上的不同取代基决定结合哪些蛋白酶，与优选的底物偏好表现出良好的相关性。IC ABP可以以敏感的方式（低至总蛋白的0.007％）在蛋白质组背景中检测其目标蛋白酶。此外，我们显示了组织蛋白质组中内源蛋白酶的活性依赖性和选择性标记。因此，这些IC代表了对丝氨酸蛋白酶已经存在的ABP的宝贵扩展，并且可能在将来阐明丝氨酸蛋白酶功能方面发挥了作用。
• Homophthalic Esters: A New Type of Reagents for the Castagnoli‐Cushman Reaction
  作者：Natalia Guranova、Olga Bakulina、Dmitry Dar'in、Grigory Kantin、Mikhail Krasavin

  DOI：10.1002/ejoc.202101281

  日期：2022.3.7

  A fundamentally new reagent space has been discovered for the Castagnoli-Cushman reaction. Cyclic anhydride has been successfully replaced with CDI-activated monoesters of homophthalic acid allowing direct preparation of tetrahydroisoquinolonic esters. Mechanistic studies suggested a new reaction pathway not involving any previously described alkoxyisocoumarines.

  已经为 Castagnoli-Cushman 反应发现了一个全新的试剂空间。环酸酐已成功地被 CDI 活化的高邻苯二甲酸单酯取代，从而可以直接制备四氢异喹诺酮酯。机理研究提出了一种不涉及任何先前描述的烷氧基异香豆素的新反应途径。
• Lactone Enolates of Isochroman-3-ones and 2-Coumaranones: Quantification of Their Nucleophilicity in DMSO and Conjugate Additions to Chalcones
  作者：Mohammad Sadeq Mousavi、Antonia Di Mola、Giovanni Pierri、Consiglia Tedesco、Magenta J. Hensinger、Aijia Sun、Yilan Wang、Peter Mayer、Armin R. Ofial、Antonio Massa

  DOI：10.1021/acs.joc.4c00277

  日期：2024.5.17

  Owing to stereoelectronic effects, lactones often deviate in reactivity from their open-chain ester analogues as demonstrated by the CH acidity (in DMSO) of 3-isochromanone (pKa = 18.8) and 2-coumaranone (pKa = 13.5), which is higher than that of ethyl phenylacetate (pKa = 22.6). We have now characterized the reactivity of the lactone enolates derived from 3-isochromanone and 2-coumaranone by following

  由于立体电子效应，内酯的反应性通常与其开链酯类似物不同，如 3-异色满酮 (p Ka = 18.8) 和 2-香豆酮 (p Ka = 13.5 )的 CH 酸度（在 DMSO 中）所证明的那样，高于苯乙酸乙酯 (p K a = 22.6)。现在，我们通过跟踪 3-异苯并二氢吡喃酮和 2-香豆酮衍生的内酯烯醇化物与对醌甲基化物和亚芳基丙二酸酯（参考亲电子试剂）在 20 °C 下在 DMSO 中的迈克尔反应动力学，表征了它们的反应性。通过 Mayr-Patz 方程 lg k 2 = s N ( N + E ) 对实验确定的二阶速率常数k 2进行评估，提供了内酯烯醇化物的亲核性参数N （和s N ）。通过将它们在迈尔亲核性尺度上的位置定位，它们的亲电反应伙伴的范围变得可预测，并且我们展示了一种新的催化方法，用于在甲苯中的相转移条件下内酯烯醇化物与查尔酮的一系列碳-碳键形成反应。
• Further characterization of a putative serine protease contributing to the γ-secretase cleavage of β-amyloid precursor protein
  作者：Marine Peuchmaur、Marie-Agnès Lacour、Jean Sévalle、Vincent Lisowski、Youness Touati-Jallabe、Fabien Rodier、Jean Martinez、Frédéric Checler、Jean-François Hernandez

  DOI：10.1016/j.bmc.2012.11.045

  日期：2013.2

  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.