(E)-4-Hydroxy-2-nonenal | 75899-68-2

• 物质功能分类: 有机原料 - 醛类化合物
• 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: (E)-4-Hydroxy-2-nonenal
• 英文别名: 4-hydroxynonenal；4-hydroxy-2-nonenal；(E)-4-hydroxynon-2-enal
• CAS: 75899-68-2
• 化学式: C₉H₁₆O₂
• 分子量: 156.225
• InChiKey: JVJFIQYAHPMBBX-FNORWQNLSA-N

物化性质

• 沸点：
  125-127 °C(Press: 2 Torr)
• 密度：
  0.941±0.06 g/cm3(Predicted)
• 溶解度：
  DMF：>50mg/mL； DMSO：>50mg/mL；乙醇：>50mg/mL； PBS pH 7.2：>1 mg/mL
• 物理描述：
  Solid

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  11
• 可旋转键数：
  6
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  37.3
• 氢给体数：
  1
• 氢受体数：
  2

ADMET

代谢

尿素毒素往往会因为饮食过量或者肾脏过滤功能不佳而在血液中积聚。大多数尿素毒素是代谢废物，通常通过尿液或粪便排出。

Uremic toxins tend to accumulate in the blood either through dietary excess or through poor filtration by the kidneys. Most uremic toxins are metabolic waste products and are normally excreted in the urine or feces.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

尿毒症毒素如4-羟基壬烯醛通过有机离子转运体（特别是OAT3）积极运输到肾脏中。尿毒症毒素水平的增加可以刺激活性氧种类的产生。这似乎是通过尿毒症毒素直接结合或抑制NADPH氧化酶（特别是肾脏和心脏中丰富的NOX4）来介导的。活性氧种类可以诱导几种不同的DNA甲基转移酶（DNMTs），这些酶参与沉默一种名为KLOTHO的蛋白质。KLOTHO被识别为在抗衰老、矿物质代谢和维生素D代谢中具有重要作用。许多研究表明，在急性或慢性肾脏疾病中，由于局部活性氧种类水平升高，KLOTHO mRNA和蛋白水平会降低。

Uremic toxins such as 4-Hydroxynonenal are actively transported into the kidneys via organic ion transporters (especially OAT3). Increased levels of uremic toxins can stimulate the production of reactive oxygen species. This seems to be mediated by the direct binding or inhibition by uremic toxins of the enzyme NADPH oxidase (especially NOX4 which is abundant in the kidneys and heart) (A7868). Reactive oxygen species can induce several different DNA methyltransferases (DNMTs) which are involved in the silencing of a protein known as KLOTHO. KLOTHO has been identified as having important roles in anti-aging, mineral metabolism, and vitamin D metabolism. A number of studies have indicated that KLOTHO mRNA and protein levels are reduced during acute or chronic kidney diseases in response to high local levels of reactive oxygen species (A7869).

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 致癌物分类

对人类不具有致癌性（未被国际癌症研究机构IARC列名）。

No indication of carcinogenicity to humans (not listed by IARC).

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 健康影响

长期暴露于尿毒症毒素可能会导致多种疾病，包括肾脏损伤、慢性肾病和心血管疾病。

Chronic exposure to uremic toxins can lead to a number of conditions including renal damage, chronic kidney disease and cardiovascular disease.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 暴露途径

内源性的，摄入，皮肤（接触）

Endogenous, Ingestion, Dermal (contact)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 症状

作为尿毒症毒素，这种化合物可以引起尿毒症综合征。尿毒症综合征可能影响身体的任何部位，并可能导致恶心、呕吐、食欲丧失和体重减轻。它还可能引起精神状态的变化，如混乱、意识减退、躁动、精神疾病、癫痫和昏迷。还可能出现异常出血，例如在非常轻微的损伤后自发或大量出血。心脏问题，如心律不齐、心脏包膜（心包）炎症和心脏压力增加，也可能出现在尿毒症综合征患者身上。由于肺部和胸壁之间的空间（胸腔积液）积聚液体导致的呼吸急促也可能存在。

As a uremic toxin, this compound can cause uremic syndrome. Uremic syndrome may affect any part of the body and can cause nausea, vomiting, loss of appetite, and weight loss. It can also cause changes in mental status, such as confusion, reduced awareness, agitation, psychosis, seizures, and coma. Abnormal bleeding, such as bleeding spontaneously or profusely from a very minor injury can also occur. Heart problems, such as an irregular heartbeat, inflammation in the sac that surrounds the heart (pericarditis), and increased pressure on the heart can be seen in patients with uremic syndrome. Shortness of breath from fluid buildup in the space between the lungs and the chest wall (pleural effusion) can also be present.

来源:Toxin and Toxin Target Database (T3DB)

安全信息

• 危险品标志：
  Xi
• 海关编码：
  2912491000
• 安全说明：
  S26,S37/39
• 危险类别码：
  R36/37/38
• 储存条件：
  -70°C

制备方法与用途

生物活性

4-羟基壬烯醛（4-HNE）是一种α，β-不饱和羟基烯醛，是氧化/亚硝化应激的生物标志物。它既是ALDH2的底物也是抑制剂，并可以调节多种信号传导过程，主要是通过与蛋白质、核酸和膜脂质中具有亲核官能团的共价加合物形成。4-羟基壬烯醛在线粒体中在癌症中起重要作用。

目标

人类内源性代谢物

体外研究

4-羟基壬烯醛既是ALDH2的底物也是抑制剂；低浓度时，由4-羟基壬烯醛引起的ALDH2抑制是可逆的，而当其浓度达到10 µM时，这种抑制则变得不可逆。4-羟基壬烯醛可以诱导抗氧化防御机制来限制自身产生，并增强细胞对抗氧化应激的保护。

4-羟基壬烯醛是脂质过氧化的产物，在病毒、细菌和哺乳动物细胞中具有致突变性和遗传毒性。它与四种DNA碱基反应，但效率不同：G > C > A > T。4-羟基壬烯醛-dG是最理想的4-羟基壬烯醛遗传毒性效应的生物标志物，并且这些加合物主要存在于核DNA中。在人类癌症中的经典例子是4-羟基壬烯醛-dG诱导的p53突变。4-羟基壬烯醛-dG加合物倾向于在p53基因第三碱基位置形成，导致基因突变并对细胞周期停滞、凋亡、DNA修复和分化等多种生物过程产生影响。

体内研究

在流体冲击损伤（FPI）后24小时，小鼠脑组织中NADPH氧化酶1（NOX1）、诱导型一氧化氮合酶（iNOS）以及4-羟基壬烯醛（4-HNE）的表达水平被分析。无论是野生型（Nrf2 +/+）还是Nrf2缺陷型（Nrf2 −/−）小鼠，在遭受15 psi损伤时，4-HNE的表达水平均显著增加，并且与未受损的小鼠相比，Nrf2 −/− KO小鼠中4-HNE的表达水平明显更高。这与iNOS结果相似，在Nrf2 −/− KO小鼠中，受伤和未受伤组的4-HNE表达水平显著高于野生型对应组动物。

反应信息

• 作为反应物：
  描述：

  (E)-4-Hydroxy-2-nonenal 在 2,2'-联吡啶 、 sodium dihydrogenphosphate 、 silica gel 作用下， 以 水 、 乙腈 为溶剂， 反应 122.0h， 生成 N,N'-diisopropyl-2-methoxy-2-pentyl-1,2-dihydropyrrol-3-one iminium
  参考文献：
  名称：

  Independent Synthesis, Solution Behavior, and Studies on the Mechanism of Formation of a Primary Amine-Derived Fluorophore Representing Cross-linking of Proteins by (E)-4-Hydroxy-2-nonenal

  摘要：

  Lipid peroxidation in aging and degenerative disease results in the production of 4-hydroxy-2-alkenals that modify proteins and give rise to both protein cross-linking and fluorophore generation. Recent model studies demonstrated that the major ex/em 360/430 fluorophore formed from (E)-4-hydroxy-2-nonenal (HNE) or (E)-4-hydroxy-2-hexenal (HHE) and protein lysine-based amine is a 2-alkyl-2-hydroxy-1,2-dihydropyrrol-3-one iminium 1:2 cross-link (1), a structure that is further confirmed here using N-15-labeling, and which has pH stability characteristics the same as those of lipofuscin pigments isolated from human tissues. Fluorophore generation represents an overall four-electron oxidation, requires dioxygen, and is enhanced by the presence of Cu(II). The HNE-propylamine-derived fluorophore 1a was independently synthesized from either 3,4-dioxononanal (8) or (E)-4-oxo-2-nonenal (13), providing further evidence for its assigned structure and clues to how it forms from HNE. Mechanistic studies on HNE-derived fluorophore formation permit ruling out the initial reversible HNE-derived Schiff base Michael adduct (17) as an intermediate. In addition, the structurally related non-cross-link 2-pentyl-2-hydroxy-1,2-dihydropyrrol-3-one 9a that forms along with 1a from 8 does not form from HNE and does: not serve as a precursor to la in the HNE-amine reaction system. A mechanism involving two 2e oxidations following initial Schiff base formation is proposed that is consistent with intermediates independently accessed from 8 and 13.

  DOI：

  10.1021/jo982523j
• 作为产物：
  描述：

  四氢吡喃 在 4-二甲氨基吡啶 、 sodium tetrahydroborate 、 sodium periodate 、 四丁基氟化铵 、 4-甲基苯磺酸吡啶 、 magnesium 、 溶剂黄146 、 calcium carbonate 、 sodium iodide 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 二甲基亚砜 为溶剂， 反应 21.5h， 生成 (E)-4-Hydroxy-2-nonenal
  参考文献：
  名称：

  Synthesis of [9-³H]-trans-4-Hydroxy-2-nonenal

  摘要：

  DOI：

  10.1021/jo972320f

文献信息

• ALDH2 ACTIVATOR
  申请人：Eisai R&D Management Co., Ltd.

  公开号：US20190231720A1

  公开（公告）日：2019-08-01

  The present invention provides a compound represented by formula ( 1 ): or pharmaceutically acceptable salt thereof, wherein X and Y are the same or different from each other and represent a hydrogen atom, a halogen atom, a C 1-6 alkyl group, or a C 1-6 alkoxy group, wherein the C 1-6 alkoxy group may be substituted with a C 1-6 alkoxy group, and Z and W are the same or different from each other and represent a hydrogen atom, a halogen atom, or a C 1-6 alkyl group.

  本发明提供了一种由下式（1）表示的化合物或其药学上可接受的盐，其中X和Y彼此相同或不同，表示氢原子、卤原子、C1-6烷基或C1-6甲氧基，其中C1-6甲氧基可以被C1-6烷氧基取代，Z和W彼此相同或不同，表示氢原子、卤原子或C1-6烷基。
• IMMUNOTHERAPY AGAINST SEVERAL TUMORS, SUCH AS LUNG CANCER, INCLUDING NSCLC
  申请人：IMMATICS BIOTECHNOLOGIES GMBH

  公开号：US20160168200A1

  公开（公告）日：2016-06-16

  The present invention relates to peptides, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated cytotoxic T cell (CTL) peptide epitopes, alone or in combination with other tumor-associated peptides that serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses. The present invention relates to more than 70 novel peptide sequences and their variants derived from HLA class I and HLA class II molecules of human tumor cells that can be used in vaccine compositions for eliciting anti-tumor immune responses.

  本发明涉及用于免疫治疗方法的肽、核酸和细胞。具体来说，本发明涉及癌症的免疫疗法。此外，本发明还涉及肿瘤相关的细胞毒性T细胞（CTL）肽表位，单独或与其他肿瘤相关肽结合，作为刺激抗肿瘤免疫反应的疫苗组成的活性药用成分。本发明涉及从人类肿瘤细胞的HLA-I类和HLA-II类分子中衍生的70多个新肽序列及其变体，可用于疫苗组成中，用于引发抗肿瘤免疫反应。
• [EN] OXADIAZOLONES AS TRANSIENT RECEPTOR POTENTIAL CHANNEL INHIBITORS<br/>[FR] OXADIAZOLONES EN TANT QU'INHIBITEURS DE CANAL POTENTIEL RÉCEPTEUR TRANSITOIRE
  申请人：HOFFMANN LA ROCHE

  公开号：WO2018096159A1

  公开（公告）日：2018-05-31

  The invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof. In addition, the present invention relates to methods of manufacturing and methods of using the compounds of formula (I) as well as pharmaceutical compositions containing such compounds. The compounds may be useful in treating diseases and conditions mediated by TRPA1, such as pain.

  该发明涉及式(I)的化合物及其药用可接受的盐。此外，本发明涉及制备方法和使用式(I)的化合物的方法，以及含有这种化合物的药物组合物。这些化合物可能在治疗由TRPA1介导的疾病和症状，如疼痛方面有用。
• HETEROCYCLIC SULFONAMIDE DERIVATIVE AND MEDICINE COMPRISING SAME
  申请人：EA PHARMA CO., LTD.

  公开号：US20160332999A1

  公开（公告）日：2016-11-17

  The present invention provides a compound represented by the formula (I): wherein each symbol is as defined in the DESCRIPTION, or a pharmaceutically acceptable salt thereof. The compound has a superior TRPA1 antagonist activity, and can provide a medicament useful for the prophylaxis or treatment of diseases involving TRPA1 antagonist and TRPA1.

  本发明提供了一种由公式(I)表示的化合物： 其中，每个符号如说明书中所定义，或者其药用可接受的盐。该化合物具有优越的TRPA1拮抗剂活性，并且可以提供一种用于预防或治疗涉及TRPA1拮抗剂和TRPA1的疾病的药物。
• [EN] SULFONYL PYRIDYL TRP INHIBITORS<br/>[FR] INHIBITEURS DE SULFONYLPYRIDYLE TRP
  申请人：HOFFMANN LA ROCHE

  公开号：WO2018029288A1

  公开（公告）日：2018-02-15

  The invention is concerned with the compounds of formula I: (I) and pharmaceutically acceptable salts thereof where R1 is a substituted or unsubstituted phenyl or a fused bicyclic comprising a substituted or unsubstituted phenyl. In addition, the present invention relates to methods of manufacturing and methods of using the compounds of formula I as well as pharmaceutical compositions containing such compounds. The compounds may be useful in treating diseases and conditions mediated by TRPA1, such as pain.

  本发明涉及公式I的化合物：(I)以及其中R1是取代的或未取代的苯基或包含取代的或未取代的苯基的并环双环的 pharmaceutically 可接受的盐。此外，本发明还涉及制造和使用公式I化合物的方法以及包含此类化合物的药物组合物。这些化合物可能对治疗由TRPA1介导的疾病和状况，如疼痛，是有用的。