(-)-2-hydroxy-N-(2-hydroxy-5-oxo-7-oxabicyclo[4.1.0]hept-3-en-3-yl)benzamide | 287194-38-1

• 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-hydroxy-N-(2-hydroxy-5-oxo-7-oxabicyclo[4.1.0]hept-3-en-3-yl)benzamide
• 英文别名: (-)-dehydroxymethylepoxyquinomicin；(-)-dehydroxymethylepoxyquinomycin；dehydroxylmethyllepoxyquinomicin；dehydroxymethylepoxyquinomicin；(-)-DHMEQ；DHMEQ；2-hydroxy-N-[(1S,2S,6S)-2-hydroxy-5-oxo-7-oxabicyclo[4.1.0]hept-3-en-3-yl]benzamide
• CAS: 287194-38-1
• 化学式: C₁₃H₁₁NO₅
• 分子量: 261.234
• InChiKey: IUOMATKBBPCLFR-TUAOUCFPSA-N

物化性质

• 溶解度：
  二甲基亚砜：≥32mg/mL（122.50mM）

计算性质

• 辛醇/水分配系数(LogP)：
  0
• 重原子数：
  19
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  99.2
• 氢给体数：
  3
• 氢受体数：
  5

安全信息

• 储存条件：
  2-8℃

制备方法与用途

生物活性

DHMEQ 拆分体是一种 NF-κB 抑制剂。与 (−)-DHMEQ 相比，DHMEQ 拆分体抑制 NF-κB 的活性较低。

靶点
NF-κB

体外研究

DHMEQ 拆分体（DHM3EQ）和 (−)-DHMEQ（DHM2EQ）均能抑制 TNF-a 引起的 NF-κB 活化。相对于 DHMEQ 拆分体，(−)-DHMEQ 更具效力且毒性较低。

体内研究

在 DBA1/J 小鼠中的 II 型胶原诱导性关节炎模型中，测试了 (−)-DHMEQ（DHM2EQ）和 DHMEQ 拆分体（DHM3EQ）的抗关节炎效果。这种动物模型广泛用于评估抗风湿药物，因为其病理特征与人类类风湿性关节炎相似。通过引发并评分关节炎，结果显示 (−)-DHMEQ 显著抑制了小鼠的 II 型胶原诱导性关节炎，而 DHMEQ 拆分体仅轻微抑制。

反应信息

• 作为反应物：
  描述：

  苄硫醇 、 (-)-2-hydroxy-N-(2-hydroxy-5-oxo-7-oxabicyclo[4.1.0]hept-3-en-3-yl)benzamide 以 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 以89%的产率得到N-((4R,5S,6S)-4-(benzylthio)-5,6-dihydroxy-3-oxocyclohex-1-en-1-yl)-2-hydroxybenzamide
  参考文献：
  名称：

  Inactivation of NF-κB Components by Covalent Binding of (−)-Dehydroxymethylepoxyquinomicin to Specific Cysteine Residues

  摘要：

  Previously, we designed and synthesized a potent NF-kappa B inhibitor, DHMEQ. Although DHMEQ showed potent anti-inflammatory and anticancer activities in animals, its molecular target has not been elucidated. In the present study, its target protein was found to be p65 and other Rel homology proteins. We found that (-)-DHMEQ bound to p65 covalently with a 1: 1 stoichiometry by conducting SPR and MALDI-TOF MS analyses. MS analysis of the chymotrypsin-digested peptide suggested the binding of (-)-DHMEQ to a Cys residue. Formation of Cys/(-)-DHMEQ adduct in the protein was supported by chemical synthesis of the adduct. Substitution of specific Cys in p65 and other Rel homology proteins resulted in the loss of (-)-DHMEQ binding. (-)-DHMEQ is the first NF-kappa B inhibitor that was proven to bind to the specific Cys by chemical methodology. These findings may explain the highly selective inhibition of NF-kappa B and the low toxic effect of (-)-DHMEQ in cells and animals.

  DOI：

  10.1021/jm8006245
• 作为产物：
  描述：

  N-(2,2-dimethoxy-5-oxo-7-oxabicyclo[4.1.0]hept-3-en-3-yl)-2-hydroxybenzamide 在 Daicel Chiralpack AD 、 三氟化硼乙醚 、 三乙酰氧基硼氢化钠 、 溶剂黄146 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 3.25h， 生成 (-)-2-hydroxy-N-(2-hydroxy-5-oxo-7-oxabicyclo[4.1.0]hept-3-en-3-yl)benzamide
  参考文献：
  名称：

  Preparation and biological activities of optically active dehydroxymethylepoxyquinomicin, a novel NF-κB inhibitor

  摘要：

  NF-kappaB is a transcription factor that induces inflammatory cytokines and anti-apoptotic proteins. We have designed a new NF-kappaB inhibitor based on the structure of the antibiotic epoxyquinomicin C. The designed compound, dehydroxymethylepoxyquinomicin (DHMEQ) was synthesized as a racemic form from 2,5-dimethoxyaniline through 5 steps. Application of racemic DHMEQ onto the chiral column (Chiralpak AD) directly gave enantiomeric DHMEQ after purification. (-)-DHMEQ was more potent than its enantiomer. (-)-DHMEQ was found to inhibit NF-kappaB activity and macrophage differentiation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in human monocyte THP-1 cells. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tet.2004.01.103

文献信息

• Unusual intramolecular N→O acyl group migration occurring during conjugation of (−)-DHMEQ with cysteine
  作者：Ikuko Kozawa、Kuniki Kato、Toshiaki Teruya、Kiyotake Suenaga、Kazuo Umezawa

  DOI：10.1016/j.bmcl.2009.07.123

  日期：2009.9

  covalently bound to a specific cysteine of NF-κB component proteins. In the course of formation of the (−)-DHMEQ and protected cysteine conjugate, we observed an unusual intramolecular N→O acyl group migration.

  以前，我们发现（-）-DHMEQ，一种特定的NF-κB抑制剂，与特定的NF-κB组分半胱氨酸共价结合。在（-）-DHMEQ和受保护的半胱氨酸缀合物形成过程中，我们观察到了异常的分子内N → O酰基迁移。
• [EN] OXABICYCLO [4.1.O]HEPT-B-EN-S-YLCARBAMOYL DERIVATIVES INHIBITING THE NUCLEAR FACTOR-KAPPA(B) - (NF-KB)<br/>[FR] DÉRIVÉS D'OXABICYCLO[4.1.0]HEPT-B-EN-S-YLCARBAMOYLE INHIBANT LE FACTEUR NUCLÉAIRE KAPPA(B)-(NF-?B)
  申请人：PROFECTUS BIOSCIENCES INC

  公开号：WO2010148042A1

  公开（公告）日：2010-12-23

  The invention relates to compounds of formula (I), formula (II), formula (III) and formula (IV),and pharmaceutically acceptable salts thereof for the treatment of cancer, inflammation, auto-immune diseases, diabetes and diabetic complications, infection, cardiovascular disease and ischemia-reperfusion injuries.

  该发明涉及式(I)、式(II)、式(III)和式(IV)的化合物，以及这些化合物的药用盐，用于治疗癌症、炎症、自身免疫疾病、糖尿病和糖尿病并发症、感染、心血管疾病和缺血再灌注损伤。
• [EN] INHIBITORS OF NF-KB<br/>[FR] INHIBITEURS DU FACTEUR NF-KB
  申请人：PROFECTUS BIOSCIENCES INC

  公开号：WO2010111460A1

  公开（公告）日：2010-09-30

  The invention relates to compounds of formulae (1) and (2), and pharmaceutically acceptable salts thereof for the treatment of cancer, inflammation, auto-immune diseases, diabetes and diabetic complications, infection, cardiovascular disease and ischemia-reperfusion injuries.

  该发明涉及式（1）和式（2）的化合物，以及其药学上可接受的盐，用于治疗癌症、炎症、自身免疫性疾病、糖尿病和糖尿病并发症、感染、心血管疾病和缺血再灌注损伤。
• [EN] BENZAMIDE AND NAPHTHAMIDE DERIVATIVES INHIBITING NUCLEAR FACTOR- KAP PA (B) - (NF-KB)<br/>[FR] DÉRIVÉS DE BENZAMIDE ET DE NAPHTAMIDE INHIBANT LE FACTEUR NUCLÉAIRE KAPPA(B) (NF-KB)
  申请人：PROFECTUS BIOSCIENCES INC

  公开号：WO2010127058A1

  公开（公告）日：2010-11-04

  The invention relates to compounds of formula (1) and formula (2), and pharmaceutically acceptable salts thereof for the treatment of cancer, inflammation, auto-immune diseases, diabetes and diabetic complications, infection, cardiovascular disease and ischemia-reperfusion injuries, wherein R1 is defined herein.

  本发明涉及式（1）和式（2）的化合物，以及其药学上可接受的盐，用于治疗癌症、炎症、自身免疫疾病、糖尿病和糖尿病并发症、感染、心血管疾病和缺血再灌注损伤，其中R1在此定义。
• MOLECULAR SIGNALING PATHWAYS TRIGGERED BY RITUXIMAB: PROGNOSTIC, DIAGNOSTIC, AND THERAPEUTIC USES
  申请人：Bonavida Benjamin

  公开号：US20070172847A1

  公开（公告）日：2007-07-26

  The present invention provides markers associated with activated molecular signaling pathways (example: p38 MAKP, NF-κB, ERK1/2, YY-1 and AKT) inhibited by rituximab in cancer cells as well as pathways activated by rituximab (such as death receptors, RKIP, PTEN) all of which are associated with the regulation of chemo and immunoresistance. The present invention provides methods of prognosis and providing a prognosis for cancer such as lymphoma, leukemia, and autoimmune disease, as well as, methods of drug discovery. These markers are also therapeutic targets for treatment of cancer resistant to conventional and experimental cancer therapeutics. Inhibition or activation of expression and/or activity of targeted gene products sensitizes resistant tumor cells to subtoxic doses of cytotoxic treatment including chemotherapy, radiation therapy, or immunotherapy and gene therapy, and the cytotoxic molecules.

  本发明提供了与被利妥昔单抗抑制的分子信号通路（例如：p38 MAKP，NF-κB，ERK1 / 2，YY-1和AKT）相关的标记，以及被利妥昔单抗激活的通路（例如死亡受体，RKIP，PTEN），所有这些都与化疗和免疫耐药性的调节有关。本发明提供了预后方法和预测淋巴瘤，白血病和自身免疫疾病等癌症的预后方法，以及药物发现的方法。这些标记也是治疗对传统和实验性癌症治疗耐药的癌症的治疗靶点。靶向基因产物的表达和/或活性的抑制或激活使耐药肿瘤细胞对亚毒性剂量的细胞毒性治疗包括化疗，放疗或免疫治疗和基因治疗以及细胞毒素变得敏感。