千里光宁氧化物 | 13268-67-2

• 分子结构分类: 有机化合物 - 生物碱及其衍生物
• 中文名称: 千里光宁氧化物
• 英文名称: senecionine N-oxide
• 英文别名: (1R,4Z,6R,7R,17R)-4-ethylidene-7-hydroxy-6,7-dimethyl-14-oxido-2,9-dioxa-14-azoniatricyclo[9.5.1.014,17]heptadec-11-ene-3,8-dione
• CAS: 13268-67-2
• 化学式: C₁₈H₂₅NO₆
• 分子量: 351.4
• InChiKey: PLGBHVNNYDZWGZ-GPUZEBNTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  25
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  90.9
• 氢给体数：
  1
• 氢受体数：
  6

安全信息

• 危险等级：
  6.1(a)
• 包装等级：
  II
• 危险类别：
  6.1(a)

制备方法与用途

生物活性方面，senecionine n-oxide 是千里光寻常型根部培养物中吡咯烷核生物碱生物合成的主要产物，并且具有抗肿瘤活性。

反应信息

• 作为反应物：
  描述：

  千里光宁氧化物 生成 (1R,4Z,6S,7R,17S)-4-ethylidene-7-hydroxy-6,7-dimethyl-2,9-dioxa-14-azatricyclo[9.5.1.014,17]heptadec-11-ene-3,8-dione
  参考文献：
  名称：

  BORSTEL, KIRSTEN V.;WITTE, LUDGER;HARTMANN, THOMAS, PHYTOCHEMISTRY, 28,(1989) N, C. 1635-1638

  摘要：

  DOI：
• 作为产物：
  描述：

  (1R,4Z,6S,7R,17S)-4-ethylidene-7-hydroxy-6,7-dimethyl-2,9-dioxa-14-azatricyclo[9.5.1.014,17]heptadec-11-ene-3,8-dione 生成 千里光宁氧化物
  参考文献：
  名称：

  WINTER, CARL K.;SEGALL, H. J.;JONES, A. DANIEL, BIOMED. AND ENVIRON. MASS SPECTROM., 15,(1988) N 5, 265-273

  摘要：

  DOI：

文献信息

• Characteristic ion clusters as determinants for the identification of pyrrolizidine alkaloid N-oxides in pyrrolizidine alkaloid-containing natural products using HPLC-MS analysis
  作者：Jianqing Ruan、Na Li、Qingsu Xia、Peter P. Fu、Shuying Peng、Yang Ye、Ge Lin

  DOI：10.1002/jms.2969

  日期：2012.3

  the mass spectra of 10 PA N-oxides and the corresponding PAs were systemically investigated using HPLC-MS to define the characteristic mass fragment ions specific to PAs and PA N-oxides. Mass spectra of toxic retronecine-type PA N-oxides exhibited two characteristic ion clusters at m/z 118-120 and 136-138. These ion clusters were produced by three unique fragmentation pathways of PA N-oxides and were

  含吡咯烷核生物碱（PA）的植物在世界范围内分布广泛。PA具有肝毒性，影响牲畜和人类。PA N氧化物通常与PA一起存在于植物中，还具有肝毒性，但效力较低。HPLC-MS通常用于分析含PA的草药，尽管在大多数情况下不提供PA参考。但是，迄今为止，没有参考标准，HPLC-MS方法无法将PA N-氧化物与PA区别开来，因为它们在质谱图中都会产生相同的特征离子。在本研究中，使用HPLC-MS系统研究了10种PA N-氧化物和相应PA的质谱，以定义对PAs和PA N-氧化物特有的特征质量碎片离子。有毒逆转录酶型PA N氧化物的质谱在m / z 118-120和136-138处显示两个特征性离子簇。这些离子簇是通过PA N-氧化物的三个独特的断裂途径产生的，并且在其相应的PA中未发现。类似地，无毒的platynecine型PA N氧化物也通过三种相似的途径断裂，从而在m / z 120-122和138-
• Species differences in the hepatic microsomal enzyme metabolism of the pyrrolizidine alkaloids
  作者：Jian-Ya Huan、Cristobal L Miranda、Donald R Buhler、Peter R Cheeke

  DOI：10.1016/s0378-4274(98)00152-0

  日期：1998.10

  cytochrome P450s and flavin-containing monooxygenases (FMO) in bioactivation and detoxification of pyrrolizidine alkaloids (PA) were studied in vitro using sheep and hamster hepatic microsomes. Chemical and immunochemical inhibition data suggested that the conversion of SN to DHP is catalyzed mainly by cytochrome P450s (68-82%), whereas the formation of SN N-oxide is carried out largely by FMO (55-71%)

  在体外测量了八种动物（绵羊、牛、沙鼠、兔子、仓鼠、日本鹌鹑、鸡、大鼠）的吡咯代谢物和 senecionine (SN) N-氧化物形成的物种差异，这些动物对吡咯里西啶生物碱 (PA) 中毒的易感性不同通过肝微粒体孵化。结果表明，吡咯代谢物的产生与动物对 PA 毒性的易感性之间没有很强的相关性。通过 (+/-)6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP) 的形成测量，仓鼠（一种抗性物种）中 PA 的活化速率远远超过 SN N-氧化物的速率形成（解毒）（DHP/N-氧化物 = 2.29）。相比之下，SN N-氧化物是绵羊的主要代谢物，绵羊是另一种抗性物种，DHP 的产量要低得多（DHP/N-氧化物 = 0.26）。使用绵羊和仓鼠肝微粒体在体外研究了细胞色素 P450 和含黄素的单加氧酶 (FMO) 在吡咯里西啶生物碱 (PA)
• Identification of Senecionine and Senecionine N-Oxide as Antifertility Constituents in Senecio vulgaris
  作者：Zhi-Ben Tu、Chohachi Konno、D. Doel Soejarto、Donald P. Waller、Audrey S. Bingel、Russell J. Molyneux、John A. Edgar、Geoffrey A. Cordell、Harry H.S. Fong

  DOI：10.1002/jps.2600770522

  日期：1988.5

  The MeOH extract of Senecio vulgaris L., administered po to rats on Days 1-10 postcoitum, significantly decreased the number of normal fetuses per pregnant rat found at autopsy on Day 16. Additional experiments showed a similar activity for its hepatotoxic constituents senecionine and senecionine N-oxide, suggesting that the latter two compounds were probably responsible for the effect seen with the

  鼠尾草在隔日后第1-10天口服给予的千里光甲醇提取物，可显着减少第16天尸检时每只怀孕大鼠的正常胎儿数量。其他实验表明，其肝毒性成分senecionine和senecionine具有相似的活性。 N-氧化物，表明后两种化合物可能是提取物中所见效果的原因。在MeOH提取物处理的仓鼠中未观察到抗生育作用。
• Evolutionary recruitment of a flavin-dependent monooxygenase for the detoxification of host plant-acquired pyrrolizidine alkaloids in the alkaloid-defended arctiid moth <i>Tyria</i> <i>jacobaeae</i>
  作者：Claudia Naumann、Thomas Hartmann、Dietrich Ober

  DOI：10.1073/pnas.082674499

  日期：2002.4.30

  Larvae of Tyria jacobaeae feed solely upon the pyrrolizidine alkaloid-containing plant Senecio jacobaea . Ingested pyrrolizidine alkaloids (PAs), which are toxic to unspecialized insects and vertebrates, are efficiently N -oxidized in the hemolymph of T. jacobaeae by senecionine N -oxygenase (SNO), a flavin-dependent monooxygenase (FMO) with a high substrate specificity for PAs. Peptide microsequences obtained from purified T. jacobaeae SNO were used to clone the corresponding cDNA, which was expressed in active form in Escherichia coli . T. jacobaeae SNO possesses a signal peptide characteristic of extracellular proteins, and it belongs to a large family of mainly FMO-like sequences of mostly unknown function, including two predicted Drosophila melanogaster gene products. The data indicate that the gene for T. jacobaeae SNO, highly specific for toxic pyrrolizidine alkaloids, was recruited from a preexisting insect-specific FMO gene family of hitherto unknown function. The enzyme allows the larvae to feed on PA-containing plants and to accumulate predation-deterrent PAs in the hemolymph.

  雅科草蛾（Tyria jacobaeae）的幼虫仅以含有吡咯啉生物碱的植物雅科草（Senecio jacobaea）为食。摄入的吡咯啉生物碱（PAs）对于非特化昆虫和脊椎动物有毒，但在雅科草蛾的血淋巴中，经由毒菊碱N-氧化酶（SNO）高效地进行N-氧化，这是一种具有高度对PAs底物特异性的黄酮依赖性单加氧酶（FMO）。从纯化的雅科草蛾SNO中获得的肽微序列被用于克隆相应的cDNA，该cDNA在大肠杆菌（Escherichia coli）中以活性形式表达。雅科草蛾SNO具有外泌蛋白特征的信号肽，并且属于一个大家族，主要是大多数未知功能的FMO样序列，包括两个预测的果蝇（Drosophila melanogaster）基因产物。数据表明，高度特异于有毒吡咯啉生物碱的雅科草蛾SNO基因，是从一个迄今未知功能的昆虫特异性FMO基因家族中招募而来的。该酶使幼虫能够以含有PA的植物为食，并在血淋巴中积累捕食威慑PAs。
• The two Faces of Pyrrolizidine Alkaloids: the Role of the Tertiary Amine and its N-Oxide in Chemical Defense of Insects with Acquired Plant Alkaloids
  作者：Rainer Lindigkeit、Andreas Biller、Markus Buch、Hans-Martin Schiebel、Michael Boppre、Thomas Hartmann

  DOI：10.1111/j.1432-1033.1997.00626.x

  日期：1997.5

  Larvae of Creatonotos transiens (Lepidoptera, Arctiidae) and Zonocerus variegatus (Orthoptera, Pyr‐gomorphidae) ingest 14C‐labeled senecionine and its N‐oxide with the same efficiency but sequester the two tracers exclusively as N‐oxide. Larvae of the non‐sequestering Spodoptera littoralis eliminate efficiently the ingested alkaloids. During feeding on the two alkaloidal forms transient levels of senecionine (but not of the N‐oxide) are built up in the haemolymph of S. littoralis larvae. Based on these results, senecionine [18O]N‐oxide was fed to C. transiens larvae and Z. variegatus adults. The senecionine N‐oxide recovered from the haemolymph of the two insects shows an almost complete loss of 18O label, indicating reduction of the orally fed N‐oxide in the guts, uptake of the tertiary alkaloid and its re‐N‐oxidation in the haemolymph. The enzyme responsible for N‐oxidation is a soluble mixed function monooxygenase. It was isolated from the haemolymph of the sequestering arctiid Tyria jacobaeue and purified to electrophoretic homogeneity. The enzyme is a flavoprotein with a native M, of 200000 and a subunit M, of 51 000. It shows a pH optimum at 7.0, has its maximal activity at a temperature of 40–45°C and an isoelectric point at pH 4.9. The reaction is strictly NADPH‐dependent (Km, 1.3 μM). From 20 pyrrolizidine alkaloids so far tested as substrates, the enyzme N‐oxidizes only alkaloids with structural elements which are essential for hepatotoxic and genotoxic pyrrolizidine alkaloids (i.e. 1,2‐double bond, esterification of the allylic hydroxyl group, presence of a second free or esterified hydroxyl group at carbon 7). A great variety of related alkaloids and xenobiotics were tested as substrate, none was accepted. The K, values of senecionine, monocrotaline and heliotrine, representing the three main types of pyrrolizidine alkaloids, are 1.3 μM, 12.5 μM and 290 μM, respectively. The novel enzyme was named senecionine N‐oxygenase (SNO). The enzyme was partially purified from two other arctiids. The three SNOs show the same general substrate specificity but differ in their affinities towards the main structural types of pyrrolizidine alkaloids. The enzymes from the two generalists (Creatonotos transiens and Arctia caja) display a broader substrate affinity than the enzyme from the specialist (Tyria jacobaeae). The two molecular forms of pyrrolizidine alkaloids, the lipophilic protoxic tertiary amine and its hydrophilic nontoxic N‐oxide are discussed in respect to their bioactivation and detoxification in mammals and their role as defensive chemicals in specialized insects. Pyrrolizidine‐alkaloid‐sequestering insects store the alkaloids as nontoxic N‐oxides which are reduced in the guts of any potential insectivore. The lipophilic tertiary alkaloid is absorbed passively and then bioactivated by cytochrome P 450 oxidase.