methyl 3-(2-bromoethoxy)-4-nitrobenzoate | 185540-61-8

• 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: methyl 3-(2-bromoethoxy)-4-nitrobenzoate
• CAS: 185540-61-8
• 化学式: C₁₀H₁₀BrNO₅
• 分子量: 304.097
• InChiKey: LUSVUXGFKQPCKU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.16
• 重原子数：
  17.0
• 可旋转键数：
  5.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  78.67
• 氢给体数：
  0.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  methyl 3-(2-bromoethoxy)-4-nitrobenzoate 在 吡啶 、 sodium hydroxide 、 氯化亚砜 、 氢溴酸 、 sodium hydride 、 potassium carbonate 、 溶剂黄146 、 苯甲醚 、 锌 作用下， 以 乙醇 、 二氯甲烷 、 N,N-二甲基乙酰胺 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 生成 dimethyl (2S)-2-[[4-[(2,4-diaminopteridin-6-yl)methyl]-2,3-dihydro-1,4-benzoxazine-7-carbonyl]amino]hexanedioate
  参考文献：
  名称：

  Antirheumatic Agents:  Novel Methotrexate Derivatives Bearing a Benzoxazine or Benzothiazine Moiety

  摘要：

  Novel methotrexate (MTX) derivatives bearing dihydro-2H-1,4-benzothiazine or dihydro-2H,1,4-benzoxazine were synthesized and tested for in vitro antiproliferative activities against human synovial cells (hSC) and human peripheral blood mononuclear cells (hPBMC) obtained from patients with rheumatoid arthritis and healthy volunteers, respectively. In vivo antiarthritic activities of these derivatives were also evaluated in a rat adjuvant arthritis model. N-[[4-[(2,4-Diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1,4-benzothiazin-7-yl]carbonyl]-L-glutamic acid (3c) exhibited more potent antiproliferative activities in hSC and hPBMC than MTX in vitro, Antiproliferative activities of N-[[4-[(2,4-diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl]carbonyl]-L-homoglutamic acid (3b) and N-[[4-[(2,4-diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1,4-benzothiazin-7-yl]carbonyl]-L-homoglutamic acid (3d) (MX-68) were comparable to that of MTX in these in vitro assays. Compounds 3b,d (MX-68) significantly suppressed progression of the adjuvant arthritis in a dose-dependent manner ranging from 0.5 to 2.5 mg/kg (po). In addition, 3d (MX-68) completely suppressed this progression at the dose of 2.5 mg/kg (po). Importantly, 3d (MX-68) having benzothiazine and homoglutamate, as expected, did not undergo polyglutamation, a process which may be responsible for the associated side effects of MTX. These results suggest that 3d (MX-68) is a potent and safe candidate antirheumatic agent, absent of the side effects of MTX.

  DOI：

  10.1021/jm9605288
• 作为产物：
  描述：

  3-羟基-4-硝基苯甲酸甲酯 、 1,2-二溴乙烷 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 以56%的产率得到methyl 3-(2-bromoethoxy)-4-nitrobenzoate
  参考文献：
  名称：

  Antirheumatic Agents:  Novel Methotrexate Derivatives Bearing a Benzoxazine or Benzothiazine Moiety

  摘要：

  Novel methotrexate (MTX) derivatives bearing dihydro-2H-1,4-benzothiazine or dihydro-2H,1,4-benzoxazine were synthesized and tested for in vitro antiproliferative activities against human synovial cells (hSC) and human peripheral blood mononuclear cells (hPBMC) obtained from patients with rheumatoid arthritis and healthy volunteers, respectively. In vivo antiarthritic activities of these derivatives were also evaluated in a rat adjuvant arthritis model. N-[[4-[(2,4-Diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1,4-benzothiazin-7-yl]carbonyl]-L-glutamic acid (3c) exhibited more potent antiproliferative activities in hSC and hPBMC than MTX in vitro, Antiproliferative activities of N-[[4-[(2,4-diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl]carbonyl]-L-homoglutamic acid (3b) and N-[[4-[(2,4-diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1,4-benzothiazin-7-yl]carbonyl]-L-homoglutamic acid (3d) (MX-68) were comparable to that of MTX in these in vitro assays. Compounds 3b,d (MX-68) significantly suppressed progression of the adjuvant arthritis in a dose-dependent manner ranging from 0.5 to 2.5 mg/kg (po). In addition, 3d (MX-68) completely suppressed this progression at the dose of 2.5 mg/kg (po). Importantly, 3d (MX-68) having benzothiazine and homoglutamate, as expected, did not undergo polyglutamation, a process which may be responsible for the associated side effects of MTX. These results suggest that 3d (MX-68) is a potent and safe candidate antirheumatic agent, absent of the side effects of MTX.

  DOI：

  10.1021/jm9605288

文献信息

• Mechanistic Studies on CysS – A Vitamin B₁₂-Dependent Radical SAM Methyltransferase Involved in the Biosynthesis of the <i>tert</i>-Butyl Group of Cystobactamid
  作者：Yuanyou Wang、Tadhg P. Begley

  DOI：10.1021/jacs.9b06454

  日期：2020.6.3

  Cobalamin (Cbl)-dependent radical SAM methyltransferases catalyze methylation reactions at non-nucleophilic centers in a wide range of substrates. CysS is a Cbl-dependent radical SAM methyltransferase involved in cystobactamid biosynthesis. This enzyme catalyzes the sequential methylation of a methoxy group to form ethoxy, i-propoxy, s-butoxy, and t-butoxy groups on a p-aminobenzoate peptidyl carrier

  钴胺素 (Cbl) 依赖性自由基 SAM 甲基转移酶可在多种底物的非亲核中心催化甲基化反应。CysS 是一种 Cbl 依赖性自由基 SAM 甲基转移酶，参与cysobactAMid 生物合成。该酶催化甲氧基的顺序甲基化，在对氨基苯甲酸肽基载体蛋白硫酯中间体上形成乙氧基、异丙氧基、仲丁氧基和叔丁氧基。这种生物合成策略使宿主粘杆菌能够生物合成 25 种囊菌酰胺类似物的组合抗生素文库。在本文中，我们描述了三个实验来阐明 CysS 如何使用 Cbl、SAM 和 [4Fe-4S] 簇来催化迭代甲基化反应：环丙基羰基重排用于捕获底物自由基并估计参与甲基转移的自由基取代反应的速率；溴乙氧基类似物用于探索活性位点地形；和氘同位素对腺苷自由基提取氢原子的影响被用来研究氢原子提取的动力学意义。基于这些实验，提出了一种修正的 CysS 机制。