diclofenac | 30124-09-5

• 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: diclofenac
• 英文别名: o-(2.6-Dichloranilino)-phenylethylakohol；2-[2-(2,6-Dichloroanilino)phenyl]ethan-1-ol；2-[2-(2,6-dichloroanilino)phenyl]ethanol
• CAS: 30124-09-5
• 化学式: C₁₄H₁₃Cl₂NO
• 分子量: 282.169
• InChiKey: NFWJEEBVQAMWHK-UHFFFAOYSA-N

物化性质

• 熔点：
  110 °C(Solv: ethyl acetate (141-78-6); hexane (110-54-3))
• 沸点：
  375.5±42.0 °C(Predicted)
• 密度：
  1.345±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  18
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  32.3
• 氢给体数：
  2
• 氢受体数：
  2

ADMET

代谢

Benzeneethanol, 2-[(2,6-二氯苯基)氨基]- (还原双氯芬酸) 已知的人类代谢物包括 4-(2,6-二氯苯基氨基)-3-(2-羟基乙基)苯酚。

Benzeneethanol, 2-[(2,6-dichlorophenyl)amino]- (reduced_diclofenac) has known human metabolites that include 4-(2,6-dichloroanilino)-3-(2-hydroxyethyl)phenol.

来源:NORMAN Suspect List Exchange

反应信息

• 作为反应物：
  描述：

  diclofenac 在 4-二甲氨基吡啶 、 四丁基氟化铵 、 sodium hydride 、 戴斯-马丁氧化剂 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 3.42h， 生成
  参考文献：
  名称：

  Diclofenac N-Derivatives as Therapeutic Agents with Anti-Inflammatory and Anti-Cancer Effect

  摘要：

  为了测试它们的抗癌和抗炎效果，合成了一系列的双氯芬酸N-衍生物（2、4、6、8c、9c、10a-c）。抗癌活性已针对三种癌细胞系进行了测定：HT29，人类结肠癌细胞；Hep-G2，人类肝细胞；以及B16-F10，小鼠黑色素瘤细胞。首先，我们确定了不同化合物的细胞毒性，发现最有效的化合物是8c对所有细胞系的作用最强，化合物4和6对人类Hep-G2和HT29细胞系的作用也很强。化合物4和8c被选中进行凋亡百分比测定、细胞周期分布和线粒体膜电位测定，因为这些产物在三种被测的癌细胞系中（B16-F10和HepG2）中呈现了最低的IC50值，并且在HT29细胞系中是三个IC50最低的产物之一。此外，化合物4和8c的凋亡诱导百分比也被测定，结果显示最高值在30%到60%之间。接下来，观察了这两种化合物对细胞周期的影响，结果显示在用产品8c处理后，细胞在G2/M细胞周期阶段的数量增加，而化合物4增加了G0/G1阶段的细胞数量，可能是通过诱导可能的分化过程。最后，为了确定这些化合物可能引发的凋亡机制，评估了线粒体电位，表明可能激活外源性凋亡机制。另一方面，我们研究了这些双氯芬酸（DCF）衍生物在脂多糖（LPS）激活的RAW 264.7巨噬细胞-单核细胞小鼠细胞上对一氧化氮（NO）产生的抑制作用。首先，我们确定了合成化合物以及DCF对这些细胞的细胞毒性。然后，使用亚细胞毒浓度来确定不同孵育时间下的NO释放。在48小时的处理后，产品2、4、8c、10a、10b和9c在20 µg·mL−1浓度下显示了最大的抗炎效果，抑制了产生的NO在60%到75%之间，并且使NO产生的浓度（IC50 NO）降低了2.5到25倍，比DCF的降低幅度更大。在这项工作中，我们首次合成并确定了八种双氯芬酸N-衍生物的抗癌和抗炎潜力。与最近的证据表明炎症可能导致所有肿瘤发生状态相一致，开发这些新的能够在非常低浓度下诱导凋亡和抗炎效果的衍生物代表了新的有效治疗策略。

  DOI：

  10.3390/ijms22105067
• 作为产物：
  描述：

  双氯芬酸 在 lithium aluminium tetrahydride 、 N,N'-二环己基碳二亚胺 作用下， 以 乙醚 、 二氯甲烷 为溶剂， 生成 diclofenac
  参考文献：
  名称：

  Design of Multifaceted Antioxidants: Shifting towards Anti-Inflammatory and Antihyperlipidemic Activity

  摘要：

  氧化应激和炎症是许多多因素疾病中共存的两种情况，如动脉粥样硬化和神经退行性疾病。因此，设计能够同时应对两个或更多治疗靶点的多功能化合物是一种吸引人的方法。在这项研究中，基本的非甾体抗炎药结构与抗氧化剂成分3,5-二叔丁基-4-羟基苯甲酸（BHB）、其还原醇3,5-二叔丁基-4-羟基苯甲醇（BHBA）或6-羟基-2,5,7,8-四甲基香豆素-2-羧酸（Trolox）进行了融合，Trolox是α-生育酚的亲水类似物。机器学习算法被用来验证设计的类似物具有的潜在双重效应（抗炎和抗氧化）。化合物1-17的衍生物通过已知的酯化方法合成，产率良好至优异，并且在体内外进行了药理学评估，评估它们的抗氧化和抗炎活性，同时选择性化合物还在体内高脂血症方案中进行了测试。此外，还研究了新化合物对脂氧合酶-3（LOX-3）的活性/结合亲和力，不仅在体外进行了研究，还通过分子对接模拟进行了研究。实验结果表明，新融合分子的抗氧化和抗炎活性比母体分子增强，而分子对接模拟验证了活性的提高并揭示了最有效抑制剂的结合模式。设计它们的目的是为多因素疾病提供一种潜在更安全和更有效的治疗方法的合理性。

  DOI：

  10.3390/molecules26164928

文献信息

• Synthesis, Structure, and Activity of Diclofenac Analogues as Transthyretin Amyloid Fibril Formation Inhibitors
  作者：Vibha B. Oza、Craig Smith、Prakash Raman、Edward K. Koepf、Hilal A. Lashuel、H. Mike Petrassi、Kyle P. Chiang、Evan T. Powers、James Sachettinni、Jeffery W. Kelly

  DOI：10.1021/jm010257n

  日期：2002.1.1

  Twelve analogues of diclofenac (1), a nonsteroidal antiinflammatory drug and known inhibitor of transthyretin (TTR) amyloid formation, were prepared and evaluated as TTR amyloid formation inhibitors. High activity was exhibited by five of the compounds. Structure-activity relationships reveal that a carboxylic acid is required for activity, but changes in its position as well as the positions of other

  制备了十二种双氯芬酸（1）（一种非甾体类抗炎药和转甲状腺素蛋白（TTR）淀粉样蛋白形成的已知抑制剂）类似物，并将其评估为TTR淀粉样蛋白形成抑制剂。五个化合物表现出高活性。结构活性关系表明，羧酸是活性所必需的，但是其位置以及其他取代基的位置变化是可以容忍的。获得了与TTR结合的四种活性化合物的高分辨率X射线晶体结构。这些证明了TTR可以在其两个结合位点内容纳配体的显着灵活性。
• [EN] SYSTEM AND METHOD FOR BIPHASIC TRANSDERMAL IONTOPHORETIC DELIVERY OF DICLOPHENAC AND OTHER THERAPEUTIC AGENTS<br/>[FR] SYSTÈME ET MÉTHODE D'ADMINISTRATION IONTOPHORÉTIQUE TRANSDERMIQUE BIPHASIQUE DE DICLOFÉNAC ET D'AUTRES AGENTS THÉRAPEUTIQUES
  申请人：INCUBE LABS LLC

  公开号：WO2020037294A1

  公开（公告）日：2020-02-20

  Various embodiments provide methods and systems for the iontophoretic transdermal delivery of therapeutic agents including NSAIDs e.g., diclophenac, to a target tissue site (TTS), using at least one electrode assembly that is positioned to be in electrical communication with a patient's skin above the TTS. In embodiments, a dose of agent is passively delivered from an assembly to the TTS during a first period, using a first current having a characteristic e.g., polarity and/or magnitude, that repels the agent out of the assembly. During a second period, a second current having a characteristic to attract the agent is used to retain the agent in the assembly such that delivery of agent into skin is minimized. Embodiments are particularly useful for delivery of agents which cause adverse effects from unwanted passive diffusion.
• Diclofenac N-Derivatives as Therapeutic Agents with Anti-Inflammatory and Anti-Cancer Effect
  作者：Alberto Galisteo、Fatin Jannus、Amalia García-García、Houssam Aheget、Sara Rojas、José A. Lupiañez、Antonio Rodríguez-Diéguez、Fernando J. Reyes-Zurita、José F. Quílez del Moral

  DOI：10.3390/ijms22105067

  日期：——

  A series of diclofenac N-derivatives (2, 4, 6, 8c, 9c, 10a-c) were synthesized in order to test their anti-cancer and anti-inflammatory effects. The anticarcinogen activity has been assayed against three cancer cell lines: HT29, human colon cancer cells; Hep-G2, human hepatic cells; and B16-F10, murine melanoma cells. First, we determined the cytotoxicity of the different compounds, finding that the most effective compound was compound 8c against all cell lines and both compounds 4 and 6 in human Hep-G2 and HT29 cell lines. Compounds 4 and 8c were selected for the percentage of apoptosis determination, cell cycle distribution, and mitochondrial membrane potential measure because these products presented the lowest IC50 values in two of the three cancer cell lines assayed (B16-F10 and HepG2), and were two of the three products with lowest IC50 in HT29 cell line. Moreover, the percentages of apoptosis induction were determined for compounds 4 and 8c, showing that the highest values were between 30 to 60%. Next, the effects of these two compounds were observed on the cellular cycle, resulting in an increase in the cell population in G2/M cell cycle phase after treatment with product 8c, whereas compound 4 increased the cells in phase G0/G1, by possible differentiation process induction. Finally, to determine the possible apoptosis mechanism triggered by these compounds, mitochondrial potential was evaluated, indicating the possible activation of extrinsic apoptotic mechanism. On the other hand, we studied the anti-inflammatory effects of these diclofenac (DCF) derivatives on lipopolysaccharide (LPS) activated RAW 264.7 macrophages-monocytes murine cells by inhibition of nitric oxide (NO) production. As a first step, we determined the cytotoxicity of the synthesized compounds, as well as DCF, against these cells. Then, sub-cytotoxic concentrations were used to determine NO release at different incubation times. The greatest anti-inflammatory effect was observed for products 2, 4, 8c, 10a, 10b, and 9c at 20 µg·mL−1 concentration after 48 h of treatment, with inhibition of produced NO between 60 to 75%, and a concentration that reduces to the 50% the production of NO (IC50 NO) between 2.5 to 25 times lower than that of DCF. In this work, we synthesized and determined for the first time the anti-cancer and anti-inflammatory potential of eight diclofenac N-derivatives. In agreement with the recent evidences suggesting that inflammation may contribute to all states of tumorigenesis, the development of these new derivatives capable of inducing apoptosis and anti-inflammatory effects at very low concentrations represent new effective therapeutic strategies against these diseases.

  为了测试它们的抗癌和抗炎效果，合成了一系列的双氯芬酸N-衍生物（2、4、6、8c、9c、10a-c）。抗癌活性已针对三种癌细胞系进行了测定：HT29，人类结肠癌细胞；Hep-G2，人类肝细胞；以及B16-F10，小鼠黑色素瘤细胞。首先，我们确定了不同化合物的细胞毒性，发现最有效的化合物是8c对所有细胞系的作用最强，化合物4和6对人类Hep-G2和HT29细胞系的作用也很强。化合物4和8c被选中进行凋亡百分比测定、细胞周期分布和线粒体膜电位测定，因为这些产物在三种被测的癌细胞系中（B16-F10和HepG2）中呈现了最低的IC50值，并且在HT29细胞系中是三个IC50最低的产物之一。此外，化合物4和8c的凋亡诱导百分比也被测定，结果显示最高值在30%到60%之间。接下来，观察了这两种化合物对细胞周期的影响，结果显示在用产品8c处理后，细胞在G2/M细胞周期阶段的数量增加，而化合物4增加了G0/G1阶段的细胞数量，可能是通过诱导可能的分化过程。最后，为了确定这些化合物可能引发的凋亡机制，评估了线粒体电位，表明可能激活外源性凋亡机制。另一方面，我们研究了这些双氯芬酸（DCF）衍生物在脂多糖（LPS）激活的RAW 264.7巨噬细胞-单核细胞小鼠细胞上对一氧化氮（NO）产生的抑制作用。首先，我们确定了合成化合物以及DCF对这些细胞的细胞毒性。然后，使用亚细胞毒浓度来确定不同孵育时间下的NO释放。在48小时的处理后，产品2、4、8c、10a、10b和9c在20 µg·mL−1浓度下显示了最大的抗炎效果，抑制了产生的NO在60%到75%之间，并且使NO产生的浓度（IC50 NO）降低了2.5到25倍，比DCF的降低幅度更大。在这项工作中，我们首次合成并确定了八种双氯芬酸N-衍生物的抗癌和抗炎潜力。与最近的证据表明炎症可能导致所有肿瘤发生状态相一致，开发这些新的能够在非常低浓度下诱导凋亡和抗炎效果的衍生物代表了新的有效治疗策略。
• Design of Multifaceted Antioxidants: Shifting towards Anti-Inflammatory and Antihyperlipidemic Activity
  作者：Ariadni Tzara、George Lambrinidis、Angeliki Kourounakis

  DOI：10.3390/molecules26164928

  日期：——

  Oxidative stress and inflammation are two conditions that coexist in many multifactorial diseases such as atherosclerosis and neurodegeneration. Thus, the design of multifunctional compounds that can concurrently tackle two or more therapeutic targets is an appealing approach. In this study, the basic NSAID structure was fused with the antioxidant moieties 3,5-di-tert-butyl-4-hydroxybenzoic acid (BHB), its reduced alcohol 3,5-di-tert-butyl- 4-hydroxybenzyl alcohol (BHBA), or 6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid (Trolox), a hydrophilic analogue of α-tocopherol. Machine learning algorithms were utilized to validate the potential dual effect (anti-inflammatory and antioxidant) of the designed analogues. Derivatives 1–17 were synthesized by known esterification methods, with good to excellent yields, and were pharmacologically evaluated both in vitro and in vivo for their antioxidant and anti-inflammatory activity, whereas selected compounds were also tested in an in vivo hyperlipidemia protocol. Furthermore, the activity/binding affinity of the new compounds for lipoxygenase-3 (LOX-3) was studied not only in vitro but also via molecular docking simulations. Experimental results demonstrated that the antioxidant and anti-inflammatory activities of the new fused molecules were increased compared to the parent molecules, while molecular docking simulations validated the improved activity and revealed the binding mode of the most potent inhibitors. The purpose of their design was justified by providing a potentially safer and more efficient therapeutic approach for multifactorial diseases.

  氧化应激和炎症是许多多因素疾病中共存的两种情况，如动脉粥样硬化和神经退行性疾病。因此，设计能够同时应对两个或更多治疗靶点的多功能化合物是一种吸引人的方法。在这项研究中，基本的非甾体抗炎药结构与抗氧化剂成分3,5-二叔丁基-4-羟基苯甲酸（BHB）、其还原醇3,5-二叔丁基-4-羟基苯甲醇（BHBA）或6-羟基-2,5,7,8-四甲基香豆素-2-羧酸（Trolox）进行了融合，Trolox是α-生育酚的亲水类似物。机器学习算法被用来验证设计的类似物具有的潜在双重效应（抗炎和抗氧化）。化合物1-17的衍生物通过已知的酯化方法合成，产率良好至优异，并且在体内外进行了药理学评估，评估它们的抗氧化和抗炎活性，同时选择性化合物还在体内高脂血症方案中进行了测试。此外，还研究了新化合物对脂氧合酶-3（LOX-3）的活性/结合亲和力，不仅在体外进行了研究，还通过分子对接模拟进行了研究。实验结果表明，新融合分子的抗氧化和抗炎活性比母体分子增强，而分子对接模拟验证了活性的提高并揭示了最有效抑制剂的结合模式。设计它们的目的是为多因素疾病提供一种潜在更安全和更有效的治疗方法的合理性。