ibuprofenoyl-CoA | 134933-17-8

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: ibuprofenoyl-CoA
• 英文别名: S-[2-[3-[[(2R)-4-[[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-4-hydroxy-3-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]oxy-2-hydroxy-3,3-dimethylbutanoyl]amino]propanoylamino]ethyl] 2-[4-(2-methylpropyl)phenyl]propanethioate
• CAS: 134933-17-8
• 化学式: C₃₄H₅₂N₇O₁₇P₃S
• 分子量: 955.811
• InChiKey: ZWOQHSZKILPKKA-TWLYMIRPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.9
• 重原子数：
  62
• 可旋转键数：
  24
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  389
• 氢给体数：
  9
• 氢受体数：
  22

反应信息

• 作为反应物：
  描述：

  谷胱甘肽 、 ibuprofenoyl-CoA 、 反应 3.0h， 生成 (2S)-2-amino-5-[[(2R)-1-(carboxymethylamino)-3-[2-[4-(2-methylpropyl)phenyl]propanoylsulfanyl]-1-oxopropan-2-yl]amino]-5-oxopentanoic acid 、
  参考文献：
  名称：

  Stereoselective Flunoxaprofen-S-acyl-glutathione Thioester Formation Mediated by Acyl-CoA Formation in Rat Hepatocytes

  摘要：

  氟诺洛芬（FLX）是一种手性非甾体抗炎药物，因担心其潜在的肝毒性而不再用于临床。FLX 通过 FLX- S -酰基-CoA 硫代酯（FLX-CoA）发生高度立体选择性手性反转，有利于 ( R )-(-)- 异构体。酸性药物的酰基-CoA硫酯衍生物是化学反应性物质，可与蛋白质亲核物和谷胱甘肽（GSH）发生反式反应。在这项研究中，我们研究了( R )-(-)- 和 ( S )-(+)-FLX 立体选择性代谢为 FLX-CoA 与随后在悬浮大鼠肝细胞中形成 FLX- S - 乙酰基谷胱甘肽（FLX-SG）的 GSH 反乙酰化之间的关系。因此，用 ( R )-(-)- 或 ( S )-(+)-FLX (100 μM) 处理肝细胞（200 万个细胞/毫升）时，可通过灵敏的液相色谱-串联质谱技术检测到 FLX-CoA 和 FLX-SG。然而，这些衍生物主要是从 ( R )-(-)-FLX 培养液中观察到的，其中 FLX-CoA 和 FLX-SG 的形成速度很快，培养 6 分钟后分别达到 42 nM 和 2.8 nM 的最大浓度。与( R )-(-)-FLX的相应培养相比，( S )-(+)-FLX培养60分钟后，FLX-CoA和FLX-SG的浓度与时间曲线下的面积分别增加了8.1%和2.7%。月桂酸（1000 μM）与( R )-(-)-FLX (10 μM)共孵育可完全抑制 FLX-CoA 的形成，并抑制 98% FLX-SG 的形成。将真品 ( R , S )-FLX-CoA (2 μM) 与 GSH (10 mM) 在缓冲液（pH 7.4，37°C）中反应，结果表明在培养 3 小时后，FLX-SG 定量形成。这些结果共同证明了在含有 ( R )-(-)-FLX 的肝细胞培养液中 GSH 的立体选择性反酰化，这与通过立体选择性 ( R )-FLX-CoA 形成的生物活化是一致的。

  DOI：

  10.1124/dmd.109.029371
• 作为产物：
  描述：

  棕榈酰氯 在 sodium iodide 、 sodium hydroxide 作用下， 以 四氢呋喃 、 丙酮 为溶剂， 反应 72.0h， 生成 ibuprofenoyl-CoA
  参考文献：
  名称：

  在水性介质中使用甲基磷酸酯合成辅酶A硫酯†

  摘要：

  辅酶A（CoA）的区域选择性S-酰化作用是在水性条件下使用各种活化的脂族和芳族羧酸作为甲基酰基磷酸酯单酯进行的。与许多疏水性活化基团不同，阴离子甲基酰基磷酸酯混合酸酐与水性溶剂更相容，使其可用于在水性介质中进行酰化反应。

  DOI：

  10.1039/c4ob02079k

文献信息

• A versatile biosynthetic approach to amide bond formation
  作者：Helena K. Philpott、Pamela J. Thomas、David Tew、Doug E. Fuerst、Sarah L. Lovelock

  DOI：10.1039/c8gc01697f

  日期：——

  The development of versatile and sustainable catalytic strategies for amide bond formation is a major objective for the pharmaceutical sector and the wider chemical industry. Herein, we report a biocatalytic approach to amide synthesis which exploits the diversity of Nature's amide bond forming enzymes, N-acyltransferases (NATs) and CoA ligases (CLs). By selecting combinations of NATs and CLs with

  通用和可持续的酰胺键形成催化策略的开发是制药行业和更广泛的化学工业的主要目标。在这里，我们报告了一种酰胺合成的生物催化方法，该方法利用了自然界中形成酰胺键的酶，N-酰基转移酶（NAT）和CoA连接酶（CL）的多样性。通过选择具有所需底物特征的NAT和CL的组合，可以以可预测的方式构建非天然的生物催化途径，以允许使用化学计量比的羧酸和胺偶联伙伴以高收率获得结构多样的仲和叔酰胺。可以使用分离的酶在体外或体内进行转化反应仅依赖于细胞产生的辅因子。这些全细胞系统的实用性通过Losmapimod的关键中间体（GW856553X）的制备规模合成得到展示，Losmapimod是一种选择性的p38促分裂原活化蛋白激酶抑制剂。
• Chiral inversion of 2-arylpropionyl-CoA esters by human α-methylacyl-CoA racemase 1A (P504S)—a potential mechanism for the anti-cancer effects of ibuprofen
  作者：Timothy J. Woodman、Pauline J. Wood、Andrew S. Thompson、Thomas J. Hutchings、Georgina R. Steel、Ping Jiao、Michael D. Threadgill、Matthew D. Lloyd

  DOI：10.1039/c1cc10763a

  日期：——

  Metabolic chiral inversion of 2-arylpropanoic acids (2-APAs;'profens'), such as ibuprofen, is important for pharmacological activity. Several 2-APA-CoA esters were good racemisation substrates for human AMACR 1A, suggesting a common chiral inversion pathway for all 2-APAs and an additional mechanism for their anti-cancer properties.

  2-芳基丙酸（2-APA;'profens'）（如布洛芬）的代谢手性转化对于药理活性很重要。几种2-APA-CoA酯是人AMACR 1A的良好消旋底物，这表明所有2-APA都具有相同的手性转化途径，并为其抗癌特性提供了另一种机制。
• Comparison of Acyl-CoA Synthetic Activities and Enantioselectivity toward 2-Arylpropanoic Acids in Firefly Luciferases
  作者：Dai-ichiro KATO、Keisuke YOKOYAMA、Yoshihiro HIRAISHI、Masahiro TAKEO、Seiji NEGORO

  DOI：10.1271/bbb.110299

  日期：2011.9.23

  Measurement of thioesterification activities for dodecanoic acid (C12) and ketoprofen was done using five firefly luciferases, from Pyrocoelia miyako (PmL), Photinus pyralis (PpL), Luciola cruciata (LcL), Hotaria parvura (HpL), and Luciola mingrelica (LmL). Among these, PmL, PpL, and LcL showed the expected thioesterification activities toward both substrates. All the enzymes exhibited (R)-enantioselectivity toward ketoprofen, which had same tendency as firefly luciferase from Luciola lateralis (LUC-H). HpL and LmL, however, did not accept ketoprofen, although they had thioesterification activity toward C12. These results indicate that the substrate acceptance of luciferases for the thioesterification reaction varies dramatically relying on the origin of firefly. Hence we focused primarily on PmL and investigated the effect of pH on enzymatic activity. In addition, by determining the kinetic parameters at various pH values, we verified that the k  cat parameter contributed to the preferential enantioselectivity of this enzyme.

  使用五种萤火虫荧光素酶测定了十二酸（C12）和酮洛芬的硫酯化活性，这五种荧光素酶分别来自Pyrocoelia miyako（PmL）、Photinus pyralis（PpL）、Luciola cruciata（LcL）、Hotaria parvura（HpL）和Luciola mingrelica（LmL）。其中，PmL、PpL 和 LcL 对两种底物都表现出预期的硫酯化活性。所有酶都对酮洛芬表现出（R）-非对映选择性，这与来自Luciola lateralis的萤火虫荧光素酶（LUC-H）具有相同的倾向。然而，HpL 和 LmL 不接受酮洛芬，尽管它们对 C12 具有硫酯化活性。这些结果表明，硫酯化反应中荧光素酶对底物的接受程度因萤火虫来源的不同而有很大差异。因此，我们主要关注 PmL，并研究了 pH 值对酶活性的影响。此外，通过测定不同 pH 值下的动力学参数，我们验证了 k cat 参数有助于该酶的优先对映选择性。
• Methods for screening compounds for use in the treatment of disease
  申请人：——

  公开号：US20040152146A1

  公开（公告）日：2004-08-05

  Methods are disclosed for screening compounds for use in the treatment of, or the identification of a clinical or biological target for, a disease. The method comprises determining the ability of the compound to influence interactions involving alpha-methylacyl-CoA racemase.

  本发明公开了用于筛选治疗疾病的化合物或确定疾病的临床或生物靶点的方法。该方法包括确定化合物影响涉及 alpha-甲基乙酰-CoA消旋酶的相互作用的能力。
• Identification of an isoform catalyzing the CoA conjugation of nonsteroidal anti-inflammatory drugs and the evaluation of the expression levels of acyl-CoA synthetases in the human liver
  作者：Hiroki Hashizume、Tatsuki Fukami、Kanji Mishima、Hiroshi Arakawa、Kenji Mishiro、Yongjie Zhang、Masataka Nakano、Miki Nakajima

  DOI：10.1016/j.bcp.2020.114303

  日期：2021.1

  Nonsteroidal anti-inflammatory drugs (NSAIDs) containing carboxylic acid are conjugated with coenzyme A (CoA) or glucuronic acid in the body. It has been suggested that these conjugates are associated with toxicities, such as liver injury and anaphylaxis, through their binding via trans-acylation to cellular proteins. Although studies on glucuronidation have progressed, studies on CoA conjugation of drugs catalyzed by acyl-CoA synthetase (ACS) enzymes are still in the early stages. This study aimed to clarify the human ACS isoforms responsible for CoA-conjugation of NSAIDs through consideration of the hepatic expression levels of ACS isoforms. We found that among 10 types of NSAIDs, propionic acid-class NSAIDs, namely, alminoprofen, flurbiprofen, ibuprofen, ketoprofen, and loxoprofen, were conjugated with CoA in the human liver, whereas NSAIDs in the other classes, including diclofenac and mefenamic acid, were not. qRT-PCR revealed that among the 26 ACS isoforms, ACSL1 was the most highly expressed in the human liver, followed by ACSM2B. The propionic acid-class NSAIDs were conjugated with CoA by recombinant human ACSL1. The protein binding abilities of the CoA conjugates and the glucuronide forms of propionic acid-class NSAIDs were compared as an index of toxicity. The CoA conjugates had stronger adduct formation with liver microsomal proteins than glucuronides for all 5 propionic acid-class NSAIDs. In conclusion, we found that propionic acid-class NSAIDs could be conjugated to CoA by ACSL1 in the human liver to form CoA conjugates, which likely cause toxicity by protein adduct formation.