diethyl (((2-methoxyphenyl)sulfonyl)methyl)phosphonate | 83050-86-6

• 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: diethyl (((2-methoxyphenyl)sulfonyl)methyl)phosphonate
• 英文别名: 1-(diethoxyphosphorylmethylsulfonyl)-2-methoxybenzene
• CAS: 83050-86-6
• 化学式: C₁₂H₁₉O₆PS
• 分子量: 322.319
• InChiKey: ZAHSBFOKXPJWLQ-UHFFFAOYSA-N

物化性质

• 熔点：
  58-61 °C
• 沸点：
  485.4±45.0 °C(Predicted)
• 密度：
  1.248±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  20
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  87.3
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  diethyl (((2-methoxyphenyl)sulfonyl)methyl)phosphonate 、 嘧啶-5-甲醛 在 正丁基锂 作用下， 以 四氢呋喃 、 环己烷 为溶剂， 反应 2.0h， 以72%的产率得到(E)-5-(2-((2'-methoxyphenyl)sulfonyl)vinyl)pyrimidine
  参考文献：
  名称：

  Optimization of Vinyl Sulfone Derivatives as Potent Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Activators for Parkinson’s Disease Therapy

  摘要：

  We previously developed a novel series of vinyl sulfones as nuclear factor erythroid 2-related factor 2 (Nrf2) activators with therapeutic potential for Parkinson's disease (PD). However, the previously developed lead compound (1) exhibited undesirable druglike properties. Here, we optimized vinyl sulfones by introducing nitrogen heterocycles to improve druglike properties. Among the synthesized compounds, 17e was the most promising drug candidate with good druglike properties. Compound 17e showed superior effects on Nrf2 activation in cell-based assays compared to compound 1 (17e: half-maximal effective concentration (EC50) = 346 nM; 1: EC50 = 530 nM). Compound 17e was further confirmed to induce expression of Nrf2-dependent antioxidant enzymes at both mRNA and protein levels. In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of PD, 17e significantly attenuated loss of tyrosine hydroxylase-immunopositive dopaminergic neurons, suppressed microglial activation, and alleviated PD-associated motor dysfunction. Thus, 17e is a novel Nrf2 activator with excellent druglike properties and represents a potential therapeutic candidate for PD.

  DOI：

  10.1021/acs.jmedchem.8b01527
• 作为产物：
  描述：

  羟甲基膦酸二乙酯 在 caesium carbonate 、 三乙胺 、 间氯过氧苯甲酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 17.0h， 生成 diethyl (((2-methoxyphenyl)sulfonyl)methyl)phosphonate
  参考文献：
  名称：

  Optimization of Vinyl Sulfone Derivatives as Potent Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Activators for Parkinson’s Disease Therapy

  摘要：

  We previously developed a novel series of vinyl sulfones as nuclear factor erythroid 2-related factor 2 (Nrf2) activators with therapeutic potential for Parkinson's disease (PD). However, the previously developed lead compound (1) exhibited undesirable druglike properties. Here, we optimized vinyl sulfones by introducing nitrogen heterocycles to improve druglike properties. Among the synthesized compounds, 17e was the most promising drug candidate with good druglike properties. Compound 17e showed superior effects on Nrf2 activation in cell-based assays compared to compound 1 (17e: half-maximal effective concentration (EC50) = 346 nM; 1: EC50 = 530 nM). Compound 17e was further confirmed to induce expression of Nrf2-dependent antioxidant enzymes at both mRNA and protein levels. In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of PD, 17e significantly attenuated loss of tyrosine hydroxylase-immunopositive dopaminergic neurons, suppressed microglial activation, and alleviated PD-associated motor dysfunction. Thus, 17e is a novel Nrf2 activator with excellent druglike properties and represents a potential therapeutic candidate for PD.

  DOI：

  10.1021/acs.jmedchem.8b01527

文献信息

• Generation of potent Nrf2 activators via tuning the electrophilicity and steric hindrance of vinyl sulfones for neuroprotection
  作者：Zi-Long Song、Yanan Hou、Feifei Bai、Jianguo Fang

  DOI：10.1016/j.bioorg.2020.104520

  日期：2021.2

  of our persistent interest in disclosing small molecules that interfere with cellular redox-regulating machinery, we reported herein the synthesis, optimization, and biological assessment of 47 vinyl sulfone scaffold-bearing small molecules, all of which exhibited robust neuroprotective effect against H2O2-mediated lesions to PC12 cells. After initial screening, the most potent neuroprotective compounds

  氧化应激不断参与范围不断扩大的神经退行性疾病的发病机制。因此，将细胞氧化应激有效抑制为氧化还原稳态是治疗或至少延缓此类疾病进展的有希望且可行的策略。Nrf2的，细胞抗氧化反应机的主协调器，负责解毒和补偿有害氧化应激通过多种抗氧化生物分子的转录激活。在我们对披露干扰细胞氧化还原调节机制的小分子的持续兴趣的框架内，我们在此报告了 47 种带有乙烯基砜支架的小分子的合成、优化和生物学评估，所有这些都对 H 表现出强大的神经保护作用2 O 2介导的PC12细胞损伤。经过初步筛选，最有效的神经保护化合物9b和9c选择具有边缘细胞毒性的细胞进行后续研究。我们的结果表明，它们的神经保护作用归因于一组抗氧化基因和相应基因产物的上调。进一步的机制研究表明，Nrf2 对9b和9c的细胞性能是必不可少的，这是由于 Nrf2 基因的沉默大大抵消了它们的保护作用。总之，在这项工作中发现的9b和9c值得进一步开发，作
• Screening, Synthesis, and In Vitro Evaluation of Vinyl Sulfones as Inhibitors of Complement-Dependent Cytotoxicity in Neuromyelitis Optica
  作者：Eun Ji Ju、Seul Ki Yeon、Jong-Hyun Park、So Young Cheon、Ji Won Choi、Taehwan Ha、Bo Ko Jang、Siwon Kim、Yong Gu Kang、Hayoung Hwang、Sung Jin Cho、Eunji Cheong、Yong Sun Bahn、Ae Nim Pae、Sung Min Kim、Ki Duk Park

  DOI：10.1002/cmdc.201500546

  日期：2016.2

  Neuromyelitis optica (NMO) is a demyelinating autoimmune disease of the optic nerve and spinal cord triggered by binding of NMO‐specific immunoglobulin G (NMO‐IgG) auto‐antibodies to the water channel aquaporin‐4 (AQP4) in astrocytes. To find potential NMO therapeutics, a screening system was established and used to identify inhibitors of NMO‐IgG‐mediated complement‐dependent cytotoxicity (CDC). The

  视神经脊髓炎（NMO）是视神经和脊髓脱髓鞘性自身免疫性疾病，由NMO特异性免疫球蛋白G（NMO-IgG）自身抗体与星形胶质细胞中水通道水通道蛋白4（AQP4）的结合触发。为了寻找潜在的NMO治疗剂，建立了筛选系统并用于鉴定NMO-IgG介导的补体依赖性细胞毒性（CDC）抑制剂。在表达人AQP4的U87-MG细胞中，对大约400种化合物的筛选产生了对CDC有抑制作用的有效命中化合物。合成了命中化合物的衍生物，并评估了它们对CDC的抑制作用。在合成的小分子中，（E）-1-（2-（（（4-甲氧基苯基）磺酰基）乙烯基）-[4-[（（3-三氟甲基）苯基]甲氧基]苯（5 c）在稳定转染的U87-MG细胞和小鼠衍生的星形胶质细胞中均显示出最有效的活性。这项研究的结果表明，靶向NMO-IgG特异性CDC的5 c可能是有用的研究工具，也是治疗NMO的治疗方法的潜在候选人。
• Discovery of Vinyl Sulfones as a Novel Class of Neuroprotective Agents toward Parkinson’s Disease Therapy
  作者：Seo Yeon Woo、Ji Hyun Kim、Mi Kyeong Moon、Se-Hee Han、Seul Ki Yeon、Ji Won Choi、Bo Ko Jang、Hyo Jung Song、Yong Gu Kang、Jin Woo Kim、Jaeick Lee、Dong Jin Kim、Onyou Hwang、Ki Duk Park

  DOI：10.1021/jm401788m

  日期：2014.2.27

  Although the etiology of Parkinson's disease (PD) remains elusive, recent studies suggest that oxidative stress contributes to the cascade leading to dopaminergic (DAergic) neurodegeneration. The Nrf2, signaling is the main pathway responsible for cellular defense system against oxidative stress. Nrf2 is a transcription factor that regulates environmental stress response by inducing expression of antioxidant enzyme genes. We have synthesized novel vinyl sulfone derivatives. They exhibited a broad range of activities in inducing HO-1, whose gene expression is under the control of Nrf2. Among them, compound 12g was confirmed to activate Nrf2 and induce expression of the Nrf2-dependent antioxidant enzymes NQO1, GCLC, GLCM, and HO-1, at both mRNA and protein levels in DAergic neuronal cells. This was accompanied by protection of DAergic neurons in both in vitro and MPTP-induced in vivo models of PD. In addition, compound 12g effectively resulted in attenuation of the PD-associated behavioral deficits in the mouse model.