4-hydroxy-trans-non-2-enal diethylacetal | 18445-69-7

• 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: 4-hydroxy-trans-non-2-enal diethylacetal
• 英文别名: 4-hydroxy-2(E)-nonen-1-al-diethylacetal；4-Hydroxy-2(E)-nonenal diethyl acetal；4-hydroxy-2-nonenal diethyl acetal；4-hydroxy-non-2-enal diethylacetal；4-hydroxynon-2-enal diethyl acetal；(RS)-1,1-diethoxynon-2-en-4-ol；(e)-4-Hydroxy-2-nonenal-diethylacetal；(E)-1,1-diethoxynon-2-en-4-ol
• CAS: 18445-69-7
• 化学式: C₁₃H₂₆O₃
• 分子量: 230.348
• InChiKey: MHUXURLVOJXADV-ZHACJKMWSA-N

物化性质

• 沸点：
  313.1±42.0 °C(Predicted)
• 密度：
  0.929±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  16
• 可旋转键数：
  10
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.85
• 拓扑面积：
  38.7
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  4-hydroxy-trans-non-2-enal diethylacetal 在 ruthenium trichloride 、 sodium periodate 作用下， 以 水 为溶剂， 反应 2.0h， 生成 2-羟基庚酸
  参考文献：
  名称：

  4-Hydroxynon-2-enal, a cytotoxic lipid peroxidation product, and its C5-analog 4-hydroxypent-2-enal: Enantioselective synthesis and stereoanalysis

  摘要：

  A stereoselective synthesis of the lipid peroxidation products 4-hydroxypent-2-enal (1a) and 4-hydroxynon-2-enal (1b) in high optical purity is presented. The configuration of 1a and b was established by Ru(III)-catalyzed oxidative degradation and subsequent stereoanalysis of the resulting alpha-hydroxy acids. It was demonstrated that 1a is configuratively stable under physiological conditions.

  DOI：

  10.1016/s0040-4020(01)81757-9
• 作为产物：
  描述：

  (+/-)-4-hydroxynon-2-ynal diethyl acetal 在 lithium aluminium tetrahydride 、 水 、 氯化铵 作用下， 以 乙醚 为溶剂， 反应 6.0h， 以65%的产率得到4-hydroxy-trans-non-2-enal diethylacetal
  参考文献：
  名称：

  脂质氢过氧化物衍生的双功能亲电子试剂 4-oxo-2(E)-壬烯醛的氘标记类似物的合成

  摘要：

  脂质氢过氧化物经过均裂分解成双功能 4-羟基-2(E)-壬烯醛和 4-氧代-2(E)-壬烯醛 (ONE)。这些双功能亲电试剂具有高反应性，可以很容易地修饰细胞内分子，包括谷胱甘肽 (GSH)、脱氧核糖核酸 (DNA) 和蛋白质。脂质氢过氧化物衍生的双功能亲电子试剂被认为有助于许多疾病的发病机制。ONE 是一种 α,β-不饱和醛，可以以多种方式与谷胱甘肽、蛋白质和 DNA 发生反应。ONE 的重同位素标记类似物不容易用于进行机理研究或用作基于质谱 (MS) 分析的内标。已开发出一种高效的、具有成本效益的方法来制备 C-9 氘标记的 ONE。此外，已经开发了一种在 C-2、C-3 或 C-2 和 C-3 处对 ONE 进行特定氘标记的方法。后一种方法涉及通过氢化铝锂或氘化铝锂选择性还原中间体炔烃，并用水或氧化氘猝灭。这些重同位素类似物的可用性将可用作使用 MS 进行定量研究的内标，并用于对 ONE

  DOI：

  10.1002/jlcr.1860

文献信息

• Design, Synthesis, ADME Properties, and Pharmacological Activities of β-Alanyl-D-histidine (D-Carnosine) Prodrugs with Improved Bioavailability
  作者：Marica Orioli、Giulio Vistoli、Luca Regazzoni、Alessandro Pedretti、Annunziata Lapolla、Giuseppe Rossoni、Renato Canevotti、Luca Gamberoni、Massimo Previtali、Marina Carini、Giancarlo Aldini

  DOI：10.1002/cmdc.201100042

  日期：2011.7.4

  The prodrugs were designed considering their expected lipophilicity and their hydrolysis predicted by docking simulations on the most important human carboxylesterase (hCES1). The stability and metabolic profile of the prodrugs were studied by incubating them with rat and human serum and liver fractions. The octyl ester of D‐CAR (compound 13) was chosen as a candidate for further pharmacological studies

  β-丙氨酰-D-组氨酸（D- CAR，天然二肽肌肽的对映异构体）是一种活性羰基化合物（RCS）的选择性强效螯合剂，对肌肽酶稳定，但在胃肠道中吸收差。本文中，我们报告了一种旨在提高D- CAR口服生物利用度的药物发现方法。在我们的研究中，我们设计，合成和评估了一系列新型亲脂性D- CAR前药。所考虑的前药可以分为两类：1）修饰了两个末端基团的衍生物，其中羧基末端始终被酯化，而氨基末端则被酰胺保护（N-乙酰基衍生物）或氨基甲酸酯（乙氧基或苄氧基衍生物）功能; 2）仅修饰一个末端的衍生物，可以是烷基酯，也可以是酰胺或氨基甲酸酯衍生物。设计前药时要考虑其预期的亲脂性和通过对接最重要的人羧酸酯酶（hCES1）的模拟预测的水解。通过将它们与大鼠和人的血清及肝部分一起孵育来研究前药的稳定性和代谢特性。由于D‐ CAR的辛基酯（化合物13）在体外可快速水解为生物活性代谢物，因此被选作进一步的药理研究对象。
• Synthesis of 4-hydroxy[4-3H]-2(E)-nonen-1-al-diethylacetal
  作者：Fabienne Bravais、Dinesh Rao、Jacques Alary、Renée C. Rao、Laurent Debrauwer、Georges Bories

  DOI：10.1002/jlcr.2580360511

  日期：1995.5

  4-Hydroxy-2(E)-nonen-1-al-diethylacetal 3 (HNE-DEA) was prepared by condensation of the Grignard compound derived from propiolaldehyde diethylacetal and n-hexanal followed by reduction of the resulting 4-hydroxy-2-nonyn-1-al-diethylacetal 2 with LiAlH4 according to the literature procedure with minor modifications. Swern oxidation [DMSO + (COCl2)] of 3 gave 30% yield of 4-oxo-2(E)-nonen-1-al-diethylacetal 5. [3H]NaBH4 and [2H]NaBH4 reduction of 5 gave rise respectively to [4-3H]HNE-DEA (specific activity 222 GBq/mmol) and [4-2H]HNE-DEA.

  4- 羟基-2(E)-壬烯-1-醛二乙缩醛 3 (HNE-DEA)的制备方法是：先用丙炔醛二乙缩醛和正己醛缩合得到的格氏化合物，然后根据文献中的方法稍加改动，用 LiAlH4 还原得到的 4- 羟基-2-壬烯-1-醛二乙缩醛 2。对 3 进行[DMSO + (COCl2)]Swern 氧化，得到 30% 产率的 4-氧代-2(E)-壬烯-1-al-二乙缩醛 5。5 的 [3H]NaBH4 和 [2H]NaBH4 还原分别得到 [4-3H]HNE-DEA（比活度 222 GBq/mmol）和 [4-2H]HNE-DEA。
• HNE Michael Adducts to Histidine and Histidine-Containing Peptides as Biomarkers of Lipid-Derived Carbonyl Stress in Urines:  LC−MS/MS Profiling in Zucker Obese Rats
  作者：Marica Orioli、Giancarlo Aldini、Maria Carmela Benfatto、Roberto Maffei Facino、Marina Carini

  DOI：10.1021/ac7016184

  日期：2007.12.1

  A new liquid chromatography−tandem mass spectrometric (LC−MS/MS) approach, based on the precursor ion scanning technique using a triple-stage quadrupole, has been developed to detect free and protein-bound histidine (His) residues modified by reactive carbonyl species (RCS) generated by lipid peroxidation. This approach has been applied to urines from Zucker obese rats, a nondiabetic animal model characterized by obesity and hyperlipidemia, where RCS formation plays a key role in the development of renal and cardiac dysfunction. The immonium ion of His at m/z 110 was used as a specific product ion of His-containing peptides to generate precursor ion spectra, followed by MS2 acquisitions of each precursor ion of interest for structural characterization. By this approach, three novel adducts, which are excreted in free form only, have been identified, two of them originating from the conjugation of 4-hydroxy-trans-2-nonenal (HNE) to His, followed by reduction/oxidation of the aldehyde:  His-1,4-dihydroxynonane (His−DHN), His-4-hydroxynonanoic acid (His−HNA), and carnosine−HNE, this last recognized in previous in vitro studies as a new potential biomarker of carbonyl stress. No free His−HNE was found in urines, which was detected only in protein hydrolysates. The same LC−MS/MS method, working in multiple reaction monitoring (MRM) mode, has been developed, validated, and applied to quantitatively profile in Zucker urines both conventional (1,4-dihydroxynonane mercapturic acid, DHN−MA) and the newly identified adducts, except His−HNA. The analytes were separated on a C12 reversed-phase column by gradient elution from 100% A (water containing 5 mM nonafluoropentanoic acid) to 80% B (acetonitrile) in 24 min at a flow rate of 0.2 mL/min and analyzed for quantification in MRM mode by applying the following precursor-to-product ion transitions m/z 322.2 → 164.1 + 130.1 (DHN−MA), m/z 314.7 → 268.2 + 110.1 (His−DHN), m/z 312.2 → 110.1 + 156.0 (His−HNE), m/z 383.1 → 266.2 + 110.1 (CAR−HNE), m/z 319.2 → 301.6 + 156.5 (H−Tyr-His−OH, internal standard). Precision and accuracy data, as well as the lower limits of quantification in urine, were highly satisfactory (from 0.01 nmol/mL for CAR−HNE, His−DHN, His−HNE, to 0.075 nmol/mL for DHN−MA). The method, applied to evaluate for the first time the advanced lipoxidation end products profile in urine from obese Zucker rats, an animal model for the metabolic syndrome, has proved to be suitable and sensitive enough for testing in vivo the carbonyl quenching ability of newly developed RCS sequestering agents.

  我们开发了一种新的液相色谱-串联质谱（LC-MS/MS）方法，该方法基于使用三级四极杆的前体离子扫描技术，用于检测由脂质过氧化产生的活性碳基（RCS）修饰的游离和蛋白结合组氨酸（His）残基。这种方法已被应用于扎克肥胖大鼠的尿液中，扎克肥胖大鼠是一种非糖尿病动物模型，以肥胖和高脂血症为特征，RCS 的形成在肾脏和心脏功能障碍的发展中起着关键作用。含 His 多肽的特异性产物离子 His 的铵离子（m/z 110）被用来生成前体离子谱，然后对每个感兴趣的前体离子进行 MS2 采集，以确定其结构特征。通过这种方法，发现了三种仅以游离形式排出体外的新型加合物，其中两种加合物来自于 4-羟基-反式-2-壬烯醛（HNE）与 His 的共轭，然后进行醛的还原/氧化反应：His-1,4-二羟基壬烷（His-DHN）、His-4-羟基壬酸（His-HNA）和肌肽-HNE，最后一种加合物在之前的体外研究中被认为是羰基压力的一种新的潜在生物标志物。尿液中未发现游离的 His-HNE，仅在蛋白质水解物中检测到。在多反应监测（MRM）模式下，开发、验证并应用了相同的 LC-MS/MS 方法，以定量分析扎克人尿液中的传统加合物（1,4-二羟基壬烷巯基酸，DHN-MA）和新发现的加合物（His-HNA 除外）。在 C12 反相色谱柱上，以 0.2 mL/min 的流速，在 24 分钟内从 100% A（含 5 mM 无氟戊酸的水）到 80% B（乙腈）进行梯度洗脱，分离分析物。2 → 164.1 + 130.1（DHN-MA），m/z 314.7 → 268.2 + 110.1（His-DHN），m/z 312.2 → 110.1 + 156.0（His-HNE），m/z 383.1 → 266.2 + 110.1（CAR-HNE），m/z 319.2 → 301.6 + 156.5（H-Tyr-His-OH，内标）。该方法的精密度和准确度以及尿液中的定量下限都非常令人满意（CAR-HNE、His-DHN、His-HNE 为 0.01 nmol/mL，DHN-MA 为 0.075 nmol/mL）。该方法首次用于评估肥胖扎克大鼠（代谢综合征的动物模型）尿液中的高级脂氧化终产物概况，证明其适用性和灵敏度足以在体内测试新开发的 RCS 封闭剂的羰基淬灭能力。
• Covalent modification of actin by 4-hydroxy-trans-2-nonenal (HNE): LC-ESI-MS/MS evidence for Cys374 Michael adduction
  作者：Giancarlo Aldini、Isabella Dalle-Donne、Giulio Vistoli、Roberto Maffei Facino、Marina Carini

  DOI：10.1002/jms.872

  日期：2005.7

  We demonstrate for the first time, by a combined mass spectrometric and computational approach, that G- and F-actin can be covalently modified by the lipid-derived aldehyde, 4-hydroxy-trans-2-nonenal, providing information on the molecular mass of modified protein and the mechanism and site of adduction. ESI-MS analysis of actin treated with different molar ratios of HNE (1 : 1 to 1 : 20) showed the formation of a protein derivative in which there was an increase of 156 Da (42028 Da) over native actin (41872 Da), consistent with the adduction of one HNE residue through Michael addition. To identify the site of HNE adduction, G- and F-actin were stabilized by NaBH4 reduction and digested with trypsin. LC-ESI-MS/MS analysis in data-dependent scan mode of the resulting peptides unequivocally indicated that Cys374 is the site of HNE adduction. Computational studies showed that the reactivity of Cys374 residue is due to a significant accessible surface and substantial thiol acidity due to the particular microenvironment surrounding Cys374. Copyright © 2005 John Wiley & Sons, Ltd.

  我们通过质谱和计算相结合的方法，首次证明了 G- 和 F- 肌动蛋白可被源自脂质的醛类--4-羟基-反式-2-壬烯醛共价修饰，从而提供了关于修饰蛋白质的分子质量以及吸附机制和部位的信息。 用不同摩尔比的 HNE（1:1 至 1:20）处理肌动蛋白后进行的 ESI-MS 分析表明，形成的蛋白质衍生物比原生肌动蛋白（41872Da）增加了 156 Da（42028Da），这与通过迈克尔加成法加持一个 HNE 残基是一致的。为了确定 HNE 加成的位点，用 NaBH4 还原法稳定 G- 和 F-肌动蛋白，并用胰蛋白酶消化。以数据依赖性扫描模式对所得肽段进行的 LC-ESI-MS/MS 分析明确表明，Cys374 是 HNE 的加成位点。计算研究表明，Cys374残基的反应性是由于Cys374周围特殊的微环境所导致的显著的可触及表面和大量的硫醇酸性。Copyright © 2005 John Wiley & Sons, Ltd. All Rights Reserved.
• Detoxification of 4-hydroxynonenal (HNE) in keratinocytes: characterization of conjugated metabolites by liquid chromatography/electrospray ionization tandem mass spectrometry
  作者：Giancarlo Aldini、Paola Granata、Marica Orioli、Enzo Santaniello、Marina Carini

  DOI：10.1002/jms.533

  日期：2003.11

  Keratinocytes are potential targets of lipid peroxidation products (α,β-unsaturated aldehydes) generated in the skin following UV exposure, among which the most abundant and toxic product is 4-hydroxy-trans-2,3-nonenal (HNE). The aim of this study was to investigate the ability of keratinocytes (NCTC2544 cell lines) to detoxify HNE, through characterization of metabolites, until now never demonstrated, using a combined analytical approach (liquid chromatography (LC) and liquid chromatography/mass spectrometry (LC/MS)). Incubation of cells with HNE (up to 200 µM) was performed in order to evaluate the ability of the cells to detoxify this toxic aldehyde, and indicated that the cell viability was maintained under these conditions. LC analysis of the extracellular media from keratinocytes incubated with 100 µM HNE shows a time-dependent decrease of HNE, disappearance from the medium within 2 h and concomitant formation of two unconjugated (phase I) metabolites, 4-hydroxy-2-nonenoic acid (HNA) and 1,4-dihydroxy-2-nonene (DHN), which were both identified and quantified by LC and accounted for 48.8 ± 4.6% of the HNE dose. Four additional metabolites were identified in the extracellular medium by reversed-phase LC coupled with electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) with positive and negative ion detection as Michael adducts (phase II metabolites), arising by the addition of the nucleophilic sulfur of glutathione (GSH) to the electrophilic C-3 of HNE, followed by oxidation–reduction enzymatic processes. The GSH–HNE conjugates were (a) S-(4-hydroxynonanal-3-yl)glutathione, (b) S-(1,4-dihydroxy-nonane-3-yl)glutathione, (c) S-(4-oxononanal-3-yl)glutathione and (d) S-(4-oxo-nonan-1-ol-3-yl)glutathione, and accounted for 52.3 ± 5.8% of the HNE dose (35 nmol mg−1 protein), as estimated indirectly by measuring the extent of cellular GSH consumption (18.7 ± 1.8 nmol mg−1 protein). The time course of HNE biotransformation was then determined by monitoring the formation of metabolites inside and outside the cell at different times after HNE addition (5–120 min). A time-dependent and almost linear formation inside the cell was observed for all the metabolites (plateau after 15 min of incubation), followed by a rapid decay and a concomitant increase in the extracellular medium (plateau of formation after 60 min). This confirms that HNE diffuses into the cell where is totally metabolized through phase I and phase II reactions to unreactive products, which are then exported outside the cell. This is the first demonstration that skin epidermal cells are able to detoxify the cytotoxic products of lipid peroxidation. Copyright © 2003 John Wiley & Sons, Ltd.

  角质形成细胞是紫外线照射后皮肤中产生的脂质过氧化产物（α,β-不饱和醛类）的潜在靶标，其中最丰富、毒性最强的产物是 4-羟基-反式-2,3-壬烯醛（HNE）。本研究的目的是采用一种综合分析方法（液相色谱法（LC）和液相色谱/质谱法（LC/MS）），通过对迄今为止从未证实过的代谢物的特征描述，研究角质形成细胞（NCTC2544 细胞系）对 HNE 的解毒能力。为了评估细胞对这种有毒醛的解毒能力，对细胞进行了 HNE（高达 200 µM）孵育，结果表明细胞在这种条件下仍能保持活力。对与 100 µM HNE 培养的角质细胞的细胞外培养基进行的液相色谱分析显示，HNE 的减少与时间有关，在 2 小时内从培养基中消失，同时形成两种未结合的（I 期）代谢物：4-羟基-2-壬烯酸（HNA）和 1,4-二羟基-2-壬烯（DHN）。通过反相液相色谱-电喷雾离子化串联质谱法（LC/ESI-MS/MS）的正负离子检测，鉴定出细胞外介质中的另外四种代谢物为迈克尔加合物（第二阶段代谢物），它们是由谷胱甘肽（GSH）的亲核硫与 HNE 的亲电 C-3 相加，然后经氧化还原酶解过程产生的。GSH-HNE 共轭物为：(a)S-(4-羟基壬醛-3-基)谷胱甘肽；(b)S-(1,4-二羟基壬烷-3-基)谷胱甘肽；(c)S-(4-氧代壬醛-3-基)谷胱甘肽；(d)S-(4-氧代-1-壬醇-3-基)谷胱甘肽。通过测量细胞 GSH 的消耗程度（18.7 ± 1.8 nmol mg-1 蛋白质），间接估计出 HNE 剂量（35 nmol mg-1 蛋白质）的 52.3 ± 5.8%。然后，在加入 HNE 后的不同时间（5-120 分钟），通过监测细胞内外代谢物的形成，确定 HNE 生物转化的时间过程。所有代谢物在细胞内的形成都与时间有关，且几乎呈线性关系（培养 15 分钟后达到峰值），随后迅速衰减，细胞外介质中的代谢物也随之增加（60 分钟后达到峰值）。这证实了 HNE 扩散到细胞内，通过 I 期和 II 期反应完全代谢为无反应产物，然后排出细胞外。这是首次证明皮肤表皮细胞能够解毒脂质过氧化的细胞毒性产物。Copyright © 2003 John Wiley & Sons, Ltd. All Rights Reserved.