O-(2,3-dichlorobenzyl)hydroxylamine | 227754-33-8

• 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: O-(2,3-dichlorobenzyl)hydroxylamine
• 英文别名: O-[(2,3-dichlorophenyl)methyl]hydroxylamine
• CAS: 227754-33-8
• 化学式: C₇H₇Cl₂NO
• 分子量: 192.045
• InChiKey: YQTUKOHDEHVKSW-UHFFFAOYSA-N

物化性质

• 沸点：
  308.9±32.0 °C(Predicted)
• 密度：
  1.374±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  11
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  35.2
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  O-(2,3-dichlorobenzyl)hydroxylamine 在 盐酸 作用下， 以 乙醚 为溶剂， 生成 O-(2,3-dichlorobenzyl)hydroxylamine hydrochloride
  参考文献：
  名称：

  O-alkylhydroxylamines as rationally-designed mechanism-based inhibitors of indoleamine 2,3-dioxygenase-1

  摘要：

  Indoleamine 2,3-dioxygenase-1 (IDO1) is a promising therapeutic target for the treatment of cancer, chronic viral infections, and other diseases characterized by pathological immune suppression. Recently important advances have been made in understanding IDO1's catalytic mechanism. Although much remains to be discovered, there is strong evidence that the mechanism proceeds through a heme-iron bound alkylperoxy transition or intermediate state. Accordingly, we explored stable structural mimics of the alkylperoxy species and provide evidence that such structures do mimic the alkylperoxy transition or intermediate state. We discovered that O-benzylhydroxylamine, a commercially available compound, is a. potent sub-micromolar inhibitor of IDO1. Structure activity studies of over forty derivatives of O-benzylhydroxylamine led to further improvement in inhibitor potency, particularly with the addition of halogen atoms to the meta position of the aromatic ring. The most potent derivatives and the lead, O-benzylhydroxylamine, have high ligand efficiency values, which are considered an important criterion for successful drug development. Notably, two of the most potent compounds demonstrated nanomolar-level cell-based potency and limited toxicity. The combination of the simplicity of the structures of these compounds and their excellent cellular activity makes them quite attractive for biological exploration of IDO1 function and antitumor therapeutic applications. (C) 2015 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2015.12.028
• 作为产物：
  描述：

  2,3-二氯苯甲醛 在 sodium tetrahydroborate 、 偶氮二甲酸二异丙酯 、 一水合肼 、 三苯基膦 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 3.5h， 生成 O-(2,3-dichlorobenzyl)hydroxylamine
  参考文献：
  名称：

  O-alkylhydroxylamines as rationally-designed mechanism-based inhibitors of indoleamine 2,3-dioxygenase-1

  摘要：

  Indoleamine 2,3-dioxygenase-1 (IDO1) is a promising therapeutic target for the treatment of cancer, chronic viral infections, and other diseases characterized by pathological immune suppression. Recently important advances have been made in understanding IDO1's catalytic mechanism. Although much remains to be discovered, there is strong evidence that the mechanism proceeds through a heme-iron bound alkylperoxy transition or intermediate state. Accordingly, we explored stable structural mimics of the alkylperoxy species and provide evidence that such structures do mimic the alkylperoxy transition or intermediate state. We discovered that O-benzylhydroxylamine, a commercially available compound, is a. potent sub-micromolar inhibitor of IDO1. Structure activity studies of over forty derivatives of O-benzylhydroxylamine led to further improvement in inhibitor potency, particularly with the addition of halogen atoms to the meta position of the aromatic ring. The most potent derivatives and the lead, O-benzylhydroxylamine, have high ligand efficiency values, which are considered an important criterion for successful drug development. Notably, two of the most potent compounds demonstrated nanomolar-level cell-based potency and limited toxicity. The combination of the simplicity of the structures of these compounds and their excellent cellular activity makes them quite attractive for biological exploration of IDO1 function and antitumor therapeutic applications. (C) 2015 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2015.12.028

文献信息

• Design and Synthesis of Terephthalic Acid‐Based Histone Deacetylase Inhibitors with Dual‐Stage Anti‐<i>Plasmodium</i>Activity
  作者：Katharina Stenzel、Ming Jang Chua、Sandra Duffy、Yevgeniya Antonova‐Koch、Stephan Meister、Alexandra Hamacher、Matthias U. Kassack、Elizabeth Winzeler、Vicky M. Avery、Thomas Kurz、Katherine T. Andrews、Finn K. Hansen

  DOI：10.1002/cmdc.201700360

  日期：2017.10.9

  work we aimed to develop parasite‐selective histone deacetylase inhibitors (HDAC) inhibitors with activity against the disease‐causing asexual blood stages of Plasmodium as well as causal prophylactic and/or transmission blocking properties. We report the design, synthesis, and biological testing of a series of 13 terephthalic acid‐based HDAC inhibitors. All compounds showed low cytotoxicity against

  在这项工作中，我们旨在开发具有选择性的寄生虫选择性组蛋白脱乙酰基酶抑制剂（HDAC）抑制剂，该抑制剂对引起疾病的无性疟原虫血液阶段具有活性，并具有因果预防和/或传播阻断特性。我们报告了一系列13种基于对苯二甲酸的HDAC抑制剂的设计，合成和生物学测试。所有化合物显示出对人胚胎肾（HEK293）细胞的细胞毒性低（IC 50：8-> 51μ米）中，用11还具有亚微摩尔的体外活性对药物敏感（3D7）和多药耐药（DD2）无性血液阶段的恶性疟原虫寄生虫（IC 50 ≈0.1-0.5μ米）。检查了一部分化合物对早期和晚期恶性疟原虫配子细胞和伯氏疟原虫外红细胞阶段寄生虫的活性。虽然仅观察到对配子细胞的中等活性（IC 50 > 2μm），但活性最高的化合物（N 1 -（（3,5-二甲基苄基）氧基）N 4-羟基对苯二甲酰胺1 f）表现出对微配子的亚微摩尔活性。伯氏疟原虫红细胞外阶段（IC 50 0.18μ米为比HepG2细胞红细胞外的形式）和>
• Isophthalic Acid-Based HDAC Inhibitors as Potent Inhibitors of HDAC8 from<i>Schistosoma mansoni</i>
  作者：Katharina Stenzel、Alokta Chakrabarti、Jelena Melesina、Finn K. Hansen、Julien Lancelot、Simon Herkenhöhner、Beate Lungerich、Martin Marek、Christophe Romier、Raymond. J. Pierce、Wolfgang Sippl、Manfred Jung、Thomas Kurz

  DOI：10.1002/ardp.201700096

  日期：2017.8

  Schistosoma mansoni histone deacetylase 8 (SmHDAC8) has been recently identified as a new potential target for the treatment of schistosomiasis. A series of newly designed and synthesized alkoxyamide‐based and hydrazide‐based HDAC inhibitors were tested for inhibitory activity against SmHDAC8 and human HDACs 1, 6, and 8. The front runner compounds showed submicromolar activity against SmHDAC8 and modest

  曼氏血吸虫组蛋白脱乙酰酶 8 (SmHDAC8) 最近被确定为治疗血吸虫病的新潜在靶点。测试了一系列新设计和合成的基于烷氧基酰胺和酰肼的 HDAC 抑制剂对 SmHDAC8 和人 HDAC 1、6 和 8 的抑制活性。直向同源物 hHDAC8。对接研究提供了对 SmHDAC8 中推定结合模式的见解，并允许对观察到的选择性曲线进行合理化。
• O-alkylhydroxylamines as rationally-designed mechanism-based inhibitors of indoleamine 2,3-dioxygenase-1
  作者：William P. Malachowski、Maria Winters、James B. DuHadaway、Ariel Lewis-Ballester、Shorouk Badir、Jenny Wai、Maisha Rahman、Eesha Sheikh、Judith M. LaLonde、Syun-Ru Yeh、George C. Prendergast、Alexander J. Muller

  DOI：10.1016/j.ejmech.2015.12.028

  日期：2016.1

  Indoleamine 2,3-dioxygenase-1 (IDO1) is a promising therapeutic target for the treatment of cancer, chronic viral infections, and other diseases characterized by pathological immune suppression. Recently important advances have been made in understanding IDO1's catalytic mechanism. Although much remains to be discovered, there is strong evidence that the mechanism proceeds through a heme-iron bound alkylperoxy transition or intermediate state. Accordingly, we explored stable structural mimics of the alkylperoxy species and provide evidence that such structures do mimic the alkylperoxy transition or intermediate state. We discovered that O-benzylhydroxylamine, a commercially available compound, is a. potent sub-micromolar inhibitor of IDO1. Structure activity studies of over forty derivatives of O-benzylhydroxylamine led to further improvement in inhibitor potency, particularly with the addition of halogen atoms to the meta position of the aromatic ring. The most potent derivatives and the lead, O-benzylhydroxylamine, have high ligand efficiency values, which are considered an important criterion for successful drug development. Notably, two of the most potent compounds demonstrated nanomolar-level cell-based potency and limited toxicity. The combination of the simplicity of the structures of these compounds and their excellent cellular activity makes them quite attractive for biological exploration of IDO1 function and antitumor therapeutic applications. (C) 2015 Elsevier Masson SAS. All rights reserved.