2-benzyl-1-oxo-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-7-carboxylic acid | 1212092-04-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 英文名称: 2-benzyl-1-oxo-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-7-carboxylic acid
• 英文别名: 3-benzyl-4-oxo-10-oxa-3-azatricyclo[5.2.1.0*1,5*]dec-8-ene-6-carboxylic acid；3-benzyl-4-oxo-10-oxa-3-azatricyclo[5.2.1.01,5]dec-8-ene-6-carboxylic acid
• CAS: 1212092-04-0
• 化学式: C₁₆H₁₅NO₄
• 分子量: 285.299
• InChiKey: JNHBKFAZBKSPLV-UHFFFAOYSA-N

物化性质

• 沸点：
  570.2±50.0 °C(Predicted)
• 密度：
  1.44±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.2
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.375
• 拓扑面积：
  66.8
• 氢给体数：
  1
• 氢受体数：
  4

安全信息

• 海关编码：
  2933790090

反应信息

• 作为反应物：
  描述：

  2-benzyl-1-oxo-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-7-carboxylic acid 在 盐酸 、 三甲基乙酰氯 、 三乙胺 作用下， 以 二氯甲烷 、 水 为溶剂， 反应 22.0h， 生成 2-benzyl-7-((R)-2-((3aR,4R,6R,7aS)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)pyrrolidine-1-carbonyl)isoindolin-1-one
  参考文献：
  名称：

  Integrated Synthetic, Biophysical, and Computational Investigations of Covalent Inhibitors of Prolyl Oligopeptidase and Fibroblast Activation Protein α

  摘要：

  Over the past decade, there has been increasing interest in covalent inhibition as a drug design strategy. Our own interest in the development of prolyl oligopeptidase (POP) and fibroblast activation protein alpha (FAP) covalent inhibitors has led us to question whether these two serine proteases were equal in terms of their reactivity toward electrophilic warheads. To streamline such investigations, we exploited both computational and experimental methods to investigate the influence of different reactive groups on both potency and binding kinetics using both our own series of POP inhibitors and others' discovered hits. A direct correlation between inhibitor reactivity and residence time was demonstrated through quantum mechanics methods and further supported by experimental studies. This computational method was also successfully applied to FAP, as an overview of known FAP inhibitors confirmed our computational predictions that more reactive warheads (e.g., boronic acids) must be employed to inhibit FAP than for POP.

  DOI：

  10.1021/acs.jmedchem.9b00642
• 作为产物：
  描述：

  N-benzyl-1-(furan-2-yl)methanimine 在 palladium 10% on activated carbon 、 氢气 作用下， 以 甲醇 、 乙醚 为溶剂， 20.0~50.0 ℃ 、5.0 MPa 条件下， 反应 24.0h， 生成 2-benzyl-1-oxo-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-7-carboxylic acid
  参考文献：
  名称：

  八氢环氧异吲哚-7-羧酸和诺坎他汀-酰胺杂化物作为诺坎他丁类似物的合成和细胞毒性。

  摘要：

  通过胺取代的呋喃与马来酸酐的狄尔斯-阿尔德反应和随后的双环[2.2.1]庚烯烯烃的还原，来获得降冰片烷din素的八氢环氧异吲哚类似物。尽管保留了已知会赋予降冰片素细胞毒性活性的羧酸盐和醚桥头素，但这些类似物均未显示出对以下11种细胞系具有明显的细胞毒性：HT29（结肠），MCF-7（乳腺癌），A2780（卵巢），H460（肺），A431（皮肤），Du145（前列腺），BE2-C（神经母细胞瘤），SJ-G2和U87（胶质母细胞瘤），MIA（胰腺）和SMA（自发鼠星形细胞瘤）。降冰伞花素合成后氨基取代系统的引入提供了容易地获得14个酸/酰胺取代的降冰伞花素类似物的途径。这些，在最初的25μm化合物筛选剂量下，只有四个显示出足够的活性，足以保证对生长抑制的全面评估。这些类似物的共同点是存在4-联苯基部分，特别是3-（2-（呋喃-2-基甲基）-3-（4-联苯基氨基）-3-氧丙基氨基甲酰基）-7-氧杂双环[2

  DOI：

  10.1002/cmdc.201900180

文献信息

• New class of hantaan virus inhibitors based on conjugation of the isoindole fragment to (+)-camphor or (−)-fenchone hydrazonesv
  作者：Olga I. Yarovaya、Kseniya S. Kovaleva、Anna A. Zaykovskaya、Liudmila N. Yashina、Nadezda S. Scherbakova、Dmitry N. Scherbakov、Sophia S. Borisevich、Fedor I. Zubkov、Alexandra S. Antonova、Roman Yu. Peshkov、Ilia V. Eltsov、Oleg V. Pyankov、Rinat A. Maksyutov、Nariman F. Salakhutdinov

  DOI：10.1016/j.bmcl.2021.127926

  日期：2021.5

  This work presents the design and synthesis of camphor, fenchone, and norcamphor N-acylhydrazone derivatives as a new class of inhibitors of the Hantaan virus, which causes haemorrhagic fever with renal syndrome (HFRS). A cytopathic model was developed for testing chemotherapeutics against the Hantaan virus, strain 76–118. In addition, a study of the antiviral activity was carried out using a pseudoviral

  这项工作介绍了樟脑、茴香酮和去甲樟脑N-酰基腙衍生物的设计和合成，作为汉坦病毒的一类新抑制剂，汉坦病毒会导致肾综合征出血热 (HFRS)。开发了一种细胞病变模型，用于测试针对汉坦病毒 76-118 毒株的化疗药物。此外，使用假病毒系统进行了抗病毒活性的研究。发现命中化合物具有显着的活性 (IC 50  = 7.6 ± 2 µM) 以及低毒性 (CC 50  > 1000 µM)。使用分子对接程序，评估与汉坦病毒核蛋白的结合，并建立合成化合物的结构与抗病毒活性之间的相关性。
• Virtual Screening and Computational Optimization for the Discovery of Covalent Prolyl Oligopeptidase Inhibitors with Activity in Human Cells
  作者：Stéphane De Cesco、Sébastien Deslandes、Eric Therrien、David Levan、Mickaël Cueto、Ralf Schmidt、Louis-David Cantin、Anthony Mittermaier、Lucienne Juillerat-Jeanneret、Nicolas Moitessier

  DOI：10.1021/jm3002839

  日期：2012.7.26

  Our docking program, Fitted, implemented in our computational platform, Forecaster, has been modified to carry out automated virtual screening of covalent inhibitors. With this modified version of the program, virtual screening and further docking-based optimization of a selected hit led to the identification of potential covalent reversible inhibitors of prolyl oligopeptidase activity. After visual inspection, a virtual hit molecule together with four analogues were selected for synthesis and made in one five chemical steps. Biological evaluations on recombinant POP and FAP alpha enzymes, cell extracts, and living cells demonstrated high potency and selectivity for POP over FAP alpha and DPPIV. Three compounds even exhibited high nanomolar inhibitory activities in intact living human cells and acceptable metabolic stability. This small set of molecules also demonstrated that covalent binding and/or geometrical constraints to the ligand/protein complex may lead to an increase in bioactivity.
• A novel alkyne-induced recyclization of 4-hydroxymethyl or 4-formyl-1H-2,3-dihydroisoindoles—an effective pathway to substituted isobenzofurans
  作者：Leonid G. Voskressensky、Larisa N. Kulikova、Alexey Kleimenov、Natalia Guranova、Tatiana N. Borisova、Alexey V. Varlamov

  DOI：10.1016/j.tetlet.2009.06.036

  日期：2009.8

  2-Alkyl or 2-benzyl-substituted 4-hydroxymethyl(formyl)isoindoles readily react with electron-deficient alkynes undergoing intramolecular cyclization to produce 1-aminomethyl-substituted isobenzofurans in good yields. (c) 2009 Elsevier Ltd. All rights reserved.
• Synthesis and Cytotoxicity of Octahydroepoxyisoindole‐7‐carboxylic Acids and Norcantharidin–Amide Hybrids as Norcantharidin Analogues
  作者：Lacey Hizartzidis、Jayne Gilbert、Christopher P. Gordon、Jennette A. Sakoff、Adam McCluskey

  DOI：10.1002/cmdc.201900180

  日期：2019.6.18

  Octahydroepoxyisoindole analogues of norcantharidin were accessed through a Diels-Alder reaction of an amine-substituted furan with maleic anhydride and subsequent reduction of the bicyclo[2.2.1]heptene olefin. Despite retention of the carboxylate and the ether bridgehead known to impart cytotoxic activity to norcantharidin, none of these analogues displayed notable cytotoxicity against the 11 cell

  通过胺取代的呋喃与马来酸酐的狄尔斯-阿尔德反应和随后的双环[2.2.1]庚烯烯烃的还原，来获得降冰片烷din素的八氢环氧异吲哚类似物。尽管保留了已知会赋予降冰片素细胞毒性活性的羧酸盐和醚桥头素，但这些类似物均未显示出对以下11种细胞系具有明显的细胞毒性：HT29（结肠），MCF-7（乳腺癌），A2780（卵巢），H460（肺），A431（皮肤），Du145（前列腺），BE2-C（神经母细胞瘤），SJ-G2和U87（胶质母细胞瘤），MIA（胰腺）和SMA（自发鼠星形细胞瘤）。降冰伞花素合成后氨基取代系统的引入提供了容易地获得14个酸/酰胺取代的降冰伞花素类似物的途径。这些，在最初的25μm化合物筛选剂量下，只有四个显示出足够的活性，足以保证对生长抑制的全面评估。这些类似物的共同点是存在4-联苯基部分，特别是3-（2-（呋喃-2-基甲基）-3-（4-联苯基氨基）-3-氧丙基氨基甲酰基）-7-氧杂双环[2
• Integrated Synthetic, Biophysical, and Computational Investigations of Covalent Inhibitors of Prolyl Oligopeptidase and Fibroblast Activation Protein α
  作者：Jessica Plescia、Stéphane De Cesco、Mihai Burai Patrascu、Jerry Kurian、Justin Di Trani、Caroline Dufresne、Alexander S. Wahba、Naëla Janmamode、Anthony K. Mittermaier、Nicolas Moitessier

  DOI：10.1021/acs.jmedchem.9b00642

  日期：2019.9.12

  Over the past decade, there has been increasing interest in covalent inhibition as a drug design strategy. Our own interest in the development of prolyl oligopeptidase (POP) and fibroblast activation protein alpha (FAP) covalent inhibitors has led us to question whether these two serine proteases were equal in terms of their reactivity toward electrophilic warheads. To streamline such investigations, we exploited both computational and experimental methods to investigate the influence of different reactive groups on both potency and binding kinetics using both our own series of POP inhibitors and others' discovered hits. A direct correlation between inhibitor reactivity and residence time was demonstrated through quantum mechanics methods and further supported by experimental studies. This computational method was also successfully applied to FAP, as an overview of known FAP inhibitors confirmed our computational predictions that more reactive warheads (e.g., boronic acids) must be employed to inhibit FAP than for POP.