2,2,6,6-tetramethylpiperidine-1-oxyl-4-yl 2-[1-(4-chlorbenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 2,2,6,6-tetramethylpiperidine-1-oxyl-4-yl 2-[1-(4-chlorbenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetate
• 英文别名: TEMPO-indomethacin
• 化学式: C₂₈H₃₂ClN₂O₅
• 分子量: 512.025
• InChiKey: QRDPUQZVMVNNAD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.9
• 重原子数：
  36
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  61.8
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  阻聚剂701 、 吲哚美辛 在 4-二甲氨基吡啶 、 N,N'-二环己基碳二亚胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 26.0h， 以73%的产率得到2,2,6,6-tetramethylpiperidine-1-oxyl-4-yl 2-[1-(4-chlorbenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetate
  参考文献：
  名称：

  通过旋转标记和EPR光谱表征活性药物成分与人血清白蛋白的结合

  摘要：

  药物与人血清白蛋白（HSA）的结合已通过自旋标记和连续波（CW）EPR光谱法进行了表征。具体而言，定量描述了化合物中官能团（FG）对白蛋白结合能力的贡献。来自不同药物类别的分子都标记有EPR活性一氧化氮自由基（旋转标记药物（SLP）），在筛选方法中，CW-EPR光谱用于研究在生理条件下以及SLP与蛋白质的比率不同时的HSA结合。CW-EPR光谱的光谱模拟允许提取缔合常数（K A）和最大数（n）每个蛋白质的结合位点。通过比较来自23个SLP的数据，可以使药物-蛋白质结合的机制以及各个位置的化学修饰对药物吸收的影响合理化。此外，可以设想具有可预测的蛋白质结合趋势的新药物修饰。

  DOI：

  10.1002/chem.201601810

文献信息

• Design, synthesis and biological evaluation of hybrid nitroxide-based non-steroidal anti-inflammatory drugs
  作者：Komba Thomas、Terry W. Moody、Robert T. Jensen、Jason Tong、Cassie L. Rayner、Nigel L. Barnett、Kathryn E. Fairfull-Smith、Lisa A. Ridnour、David A. Wink、Steven E. Bottle

  DOI：10.1016/j.ejmech.2018.01.077

  日期：2018.3

  Dual-acting hybrid anti-oxidant/anti-inflammatory agents were developed employing the principle of pharmacophore hybridization. Hybrid agents were synthesized by combining stable anti-oxidant nitroxides with conventional non-steroidal anti-inflammatory drugs (NSAIDs). Several of the hybrid nitroxide-NSAID conjugates displayed promising anti-oxidant and anti-inflammatory effects on two Non-Small Cell

  利用药效团杂交原理开发了双效混合抗氧化剂/抗炎剂。通过将稳定的抗氧化剂硝基氧与传统的非甾体抗炎药（NSAID）相结合来合成混合药物。几种混合硝基氧-NSAID 缀合物对两种非小细胞肺癌 (NSCLC) 细胞（A549 和 NCI-H1299）以及改善 661 W 视网膜细胞诱导的氧化应激表现出良好的抗氧化和抗炎作用。一种酯连接的硝基氧-阿司匹林类似物 ( 27 ) 比母体化合物（阿司匹林）具有更好的抗炎作用（环氧合酶抑制），并且还表现出与抗氧化剂 Tempol 相似的活性氧清除活性。此外，与抗炎药物吲哚美辛 ( 39 ) 连接的硝基氧化物可显着改善氧化应激对 661 W 视网膜神经元的影响，其功效大于或等于抗氧化剂叶黄素。混合缀合物的其他例子显示出有希望的抗癌活性，正如它们对 A549 NSCLC 细胞增殖的抑制作用所证明的那样。
• NITROXIDE MODIFIED NON-STEROIDAL ANTI-INFLAMMATORY COMPOUNDS AND USES THEREOF IN THE TREATMENT AND PREVENTION OF DISEASES OR DISORDERS
  申请人：Wink David A.

  公开号：US20120263650A1

  公开（公告）日：2012-10-18

  Disclosed are nitroxide modified NSAID compounds of the formula (I) or a pharmaceutically acceptable salt or enantiomer thereof: in which R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and n are defined herein and pharmaceutical compositions thereof. Further disclosed is a method of treating or preventing various disorders, such as inflammation, cancer, diabetes, a cardiovascular disorder, weight gain, polyps, and/or chronic pain, in a patient comprising administering an effective amount of a compound or pharmaceutically acceptable salt or enantiomer of formula (I). A method of imaging the compound or pharmaceutically acceptable salt or enantiomer of formula (I) in the body of the animal is also provided.

  揭示了具有以下结构式（I）的硝基氧自由基修饰的NSAID化合物或其药用盐或对映体：其中R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11和n在此处被定义，并其药物组合物。进一步揭示了一种治疗或预防各种疾病的方法，如炎症、癌症、糖尿病、心血管疾病、体重增加、息肉和/或慢性疼痛，在患者中包括给予化合物或结构式（I）的药用盐或对映体的有效量。还提供了一种在动物体内成像化合物或结构式（I）的药用盐或对映体的方法。
• Nitroxide derivatives of non-steroidal anti-inflammatory drugs exert anti-inflammatory and superoxide dismutase scavenging properties in A459 cells
  作者：Wilmarie Flores-Santana、Terry Moody、Weibin Chen、Michael J Gorczynski、Mai E Shoman、Carlos Velázquez、Angela Thetford、James B Mitchell、Murali K Cherukuri、S Bruce King、David A Wink

  DOI：10.1111/j.1476-5381.2011.01527.x

  日期：2012.2.2

  BACKGROUND AND PURPOSEInflammation and reactive oxygen species are associated with the promotion of various cancers. The use of non‐steroidal anti‐inflammatory drugs (NSAIDs) in cancer prevention treatments has been promising in numerous cancers. We report the evaluation of NSAIDs chemically modified by the addition of a redox‐active nitroxide group. TEMPO‐aspirin (TEMPO‐ASA) and TEMPO‐indomethacin (TEMPO‐IND) were synthesized and evaluated in the lung cancer cell line A549.EXPERIMENTAL APPROACHESWe evaluated physico‐chemical properties of TEMPO‐ASA and TEMPO‐IND by electron paramagnetic resonance and cyclic voltammetry. Superoxide dismutase‐like properties was assayed by measuring cytochrome c reduction and anti‐inflammatory effects were assayed by measuring production of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4). MTT proliferation assay and clonogenic assay were evaluated in the A549 lung carcinoma cell line. Maximum tolerated doses (MTD) and acute ulcerogenic index were also evaluated in in vivo.KEY RESULTSMTD were: TEMPO (140 mg·kg−1), ASA (100 mg·kg−1), indomethacin (5 mg·kg−1), TEMPO‐ASA (100 mg·kg−1) and TEMPO‐IND (40 mg·kg−1). While TEMPO‐ASA was as well tolerated as ASA, TEMPO‐IND showed an eightfold improvement over indomethacin. TEMPO‐IND showed markedly less gastric toxicity than the parent NSAID. Both TEMPO‐ASA and TEMPO‐IND inhibited production of PGE2 and LTB4 in A549 cells with maximum effects at 100 µg·mL−1 or 10 µg·mL−1 respectively.CONCLUSIONS AND IMPLICATIONSThe nitroxide‐NSAIDs retained superoxide scavenging capacity of the parent nitroxide and anti‐inflammatory effects, inhibiting cyclooxygenase and 5‐lipoxygenase enzymes. These redox‐modified NSAIDs might be potential drug candidates, as they exhibit the pharmacological properties of the parent NSAID with antioxidant activity decreasing NSAID‐associated toxicity.
• Characterizing Active Pharmaceutical Ingredient Binding to Human Serum Albumin by Spin-Labeling and EPR Spectroscopy
  作者：Till Hauenschild、Jörg Reichenwallner、Volker Enkelmann、Dariush Hinderberger

  DOI：10.1002/chem.201601810

  日期：2016.8.26

  Drug binding to human serum albumin (HSA) has been characterized by a spin‐labeling and continuous‐wave (CW) EPR spectroscopic approach. Specifically, the contribution of functional groups (FGs) in a compound on its albumin‐binding capabilities is quantitatively described. Molecules from different drug classes are labeled with EPR‐active nitroxide radicals (spin‐labeled pharmaceuticals (SLPs)) and

  药物与人血清白蛋白（HSA）的结合已通过自旋标记和连续波（CW）EPR光谱法进行了表征。具体而言，定量描述了化合物中官能团（FG）对白蛋白结合能力的贡献。来自不同药物类别的分子都标记有EPR活性一氧化氮自由基（旋转标记药物（SLP）），在筛选方法中，CW-EPR光谱用于研究在生理条件下以及SLP与蛋白质的比率不同时的HSA结合。CW-EPR光谱的光谱模拟允许提取缔合常数（K A）和最大数（n）每个蛋白质的结合位点。通过比较来自23个SLP的数据，可以使药物-蛋白质结合的机制以及各个位置的化学修饰对药物吸收的影响合理化。此外，可以设想具有可预测的蛋白质结合趋势的新药物修饰。