O²-acetoxymethyl-1-(N-ethyl-N-methylamino)diazen-1-ium-1,2-diolate (E)-3-(4-methanesulfonylphenyl)-2-(4-methoxyphenyl)acrylate | 1029146-28-8

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 英文名称: O²-acetoxymethyl-1-(N-ethyl-N-methylamino)diazen-1-ium-1,2-diolate (E)-3-(4-methanesulfonylphenyl)-2-(4-methoxyphenyl)acrylate
• 英文别名: (Z)-acetyloxymethoxyimino-[2-[(E)-2-(4-methoxyphenyl)-3-(4-methylsulfonylphenyl)prop-2-enoyl]oxyethyl-methylamino]-oxidoazanium
• CAS: 1029146-28-8
• 化学式: C₂₃H₂₇N₃O₉S
• 分子量: 521.548
• InChiKey: XZFHWVLISFWLRJ-GCXIQGEKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  36
• 可旋转键数：
  14
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  158
• 氢给体数：
  0
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  O2-acetoxymethyl-1-[N-(2-methylsulfonyloxyethyl)-N-methylamino]diazen-1-ium-1,2-diolate 、 (E)-2-(4-methoxyphenyl)-3-(4-methylsulfonylphenyl)prop-2-enoic acid 在 sodium carbonate 作用下， 以 六甲基磷酰三胺 为溶剂， 反应 91.0h， 以32%的产率得到O²-acetoxymethyl-1-(N-ethyl-N-methylamino)diazen-1-ium-1,2-diolate (E)-3-(4-methanesulfonylphenyl)-2-(4-methoxyphenyl)acrylate
  参考文献：
  名称：

  Diazen-1-ium-1,2-diolated and nitrooxyethyl nitric oxide donor ester prodrugs of anti-inflammatory (E)-2-(aryl)-3-(4-methanesulfonylphenyl)acrylic acids: Synthesis, cyclooxygenase inhibition, and nitric oxide release studies

  摘要：

  A new group of hybrid nitric oxide-releasing anti-inflammatory drugs wherein an O-2-acetoxyrnethyl-1-(N-ethyl-N-methylamino)diazen-1-ium-1,2-diolate (11a-d), or 2-nitrooxyethyl (12a-d), (NO)-N-center dot-donor moiety is attached directly to the carboxylic acid group of (E)-3-(4-methanesulfonylphenyl)-2-(phenyl)acrylic acids were synthesized. The 2-nitrooxyethyl ester prodrugs (12a-d) all exhibited in vitro inhibitory activity against the cyclooxygenase-2 (COX-2) isozyme (IC50 = 0.07-2.8 mu M range). All compounds released a low amount of (NO)-N-center dot upon incubation with phosphate buffer (PBS) at pH 7.4 (1.0-4.8% range). In comparison, the percentage (NO)-N-center dot released was significantly higher (76.2-83.0% range) when the diazen-1-ium-1,2-diolate ester prodrugs were incubated in the presence of rat serum, or moderately higher (7.6-10.1% range) when the nitrooxyethyl ester prodrugs were incubated in the presence Of L-cysteine. These incubation studies suggest that both WO and the parent anti-inflammatory (E)-3-(4-methanesulfonylphenyl)-2-(phenyl)acrylic acid would be released upon in vivo cleavage by non-specific serum esterases in the case of the diazen-1-ium-1,2-diolate esters (11a-d), or interaction with systemic thiols in the case of the nitrate esters (12a-d). O-2-Acetoxymethyl-1-(N-ethyl-N-methylamino)diazen-1-ium-1,2-diolate (E)-3-(4-methanesulfonylphenyl)-2-phenylacrylate (11a) released 83% of the theoretical maximal release of 2 molecules of (NO)-N-center dot/molecule of the parent hybrid ester prodrug upon incubation with rat serum. Hybrid ester anti-inflammatory/(NO)-N-center dot donor prodrugs offer a potential drug design concept targeted toward the development of anti-inflammatory drugs that are devoid of adverse ulcerogenic and/or cardiovascular effects. (C) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2007.12.006

文献信息

• Diazen-1-ium-1,2-diolated and nitrooxyethyl nitric oxide donor ester prodrugs of anti-inflammatory (E)-2-(aryl)-3-(4-methanesulfonylphenyl)acrylic acids: Synthesis, cyclooxygenase inhibition, and nitric oxide release studies
  作者：Khaled R.A. Abdellatif、Morshed Alam Chowdhury、Ying Dong、Qiao-Hong Chen、Edward E. Knaus

  DOI：10.1016/j.bmc.2007.12.006

  日期：2008.3.15

  A new group of hybrid nitric oxide-releasing anti-inflammatory drugs wherein an O-2-acetoxyrnethyl-1-(N-ethyl-N-methylamino)diazen-1-ium-1,2-diolate (11a-d), or 2-nitrooxyethyl (12a-d), (NO)-N-center dot-donor moiety is attached directly to the carboxylic acid group of (E)-3-(4-methanesulfonylphenyl)-2-(phenyl)acrylic acids were synthesized. The 2-nitrooxyethyl ester prodrugs (12a-d) all exhibited in vitro inhibitory activity against the cyclooxygenase-2 (COX-2) isozyme (IC50 = 0.07-2.8 mu M range). All compounds released a low amount of (NO)-N-center dot upon incubation with phosphate buffer (PBS) at pH 7.4 (1.0-4.8% range). In comparison, the percentage (NO)-N-center dot released was significantly higher (76.2-83.0% range) when the diazen-1-ium-1,2-diolate ester prodrugs were incubated in the presence of rat serum, or moderately higher (7.6-10.1% range) when the nitrooxyethyl ester prodrugs were incubated in the presence Of L-cysteine. These incubation studies suggest that both WO and the parent anti-inflammatory (E)-3-(4-methanesulfonylphenyl)-2-(phenyl)acrylic acid would be released upon in vivo cleavage by non-specific serum esterases in the case of the diazen-1-ium-1,2-diolate esters (11a-d), or interaction with systemic thiols in the case of the nitrate esters (12a-d). O-2-Acetoxymethyl-1-(N-ethyl-N-methylamino)diazen-1-ium-1,2-diolate (E)-3-(4-methanesulfonylphenyl)-2-phenylacrylate (11a) released 83% of the theoretical maximal release of 2 molecules of (NO)-N-center dot/molecule of the parent hybrid ester prodrug upon incubation with rat serum. Hybrid ester anti-inflammatory/(NO)-N-center dot donor prodrugs offer a potential drug design concept targeted toward the development of anti-inflammatory drugs that are devoid of adverse ulcerogenic and/or cardiovascular effects. (C) 2007 Elsevier Ltd. All rights reserved.