天芥菜定 | 520-63-8

• 分子结构分类: 有机化合物 - 生物碱及其衍生物
• 中文名称: 天芥菜定
• 英文名称: (+)-heliotridine
• 英文别名: heliotridine；hellotridine；(7aR)-7-Hydroxymethyl-(7ar)-2,3,5,7a-tetrahydro-1H-pyrrolizin-1c-ol；6(S)-hydroxy-4-hydroxymethyl-1-aza-bicyclo(3.3.0)octane；(1S,8R)-7-(hydroxymethyl)-2,3,5,8-tetrahydro-1H-pyrrolizin-1-ol
• CAS: 520-63-8
• 化学式: C₈H₁₃NO₂
• 分子量: 155.197
• InChiKey: HJSJELVDQOXCHO-JGVFFNPUSA-N

物化性质

• 熔点：
  58 °C
• 沸点：
  291.3±40.0 °C(Predicted)
• 密度：
  1.29±0.1 g/cm3(Predicted)
• 溶解度：
  In water, 1X10+6 mg/L @ 25 °C /Estimated/
• 蒸汽压力：
  1.5X10-5 mm Hg @ 25 °C /Estimated/
• 旋光度：
  SPECIFIC OPTICAL ROTATION: 124 DEG (ETHANOL, 1%)
• 解离常数：
  pKa= 9.01 +/- 0.05

计算性质

• 辛醇/水分配系数(LogP)：
  -1.3
• 重原子数：
  11
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  43.7
• 氢给体数：
  2
• 氢受体数：
  3

ADMET

代谢

向大鼠给药这些生物碱后，次裂碱和毛果芸香碱的水解产物——赫尔利奥特里丁，以N-氧化物形式被大量排出。

Heliotridine, the hydrolysis product from heliotrine and lasiocarpine, was excreted in the form of the N-oxide in larger quantities after the administration of each of these alkaloids /to rats/.

来源:Hazardous Substances Data Bank (HSDB)

代谢

.../和/ 海里奥特里丁，40% ...

The pa /pyrrolizidine alkaloids/, like many other foreign substances, undergo metab changes in animal body by more than one pathway. ... The known metabolites represent products of n-oxidation and dehydrogenation of pyrrolizidine moiety, of o-demethylation of methoxy groups when these are present in acidic moiety, and products of hydrolysis of ester linkages. ... The part of the administered dose that is excreted in the urine as the unchanged parent alkaloid depends mainly on its basic properties and water solubility. Lasiocarpine is excreted in trace quantities.../and/ heliotridine, 40%...

来源:Hazardous Substances Data Bank (HSDB)

代谢

动物研究的证据表明，肝毒性是由于肝细胞中的混合功能氧化酶形成有毒的吡咯代谢物所致。

Evidence from animal studies suggests that the hepatotoxicity is due to the formation of toxic pyrrolic metabolites by the mixed function oxidases of liver cells.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在给予一些吡咯里西啶生物碱和半合成衍生物的大鼠肝脏中测量了吡咯代谢物的水平。基于海绿碱的生物碱产生的吡咯比类似的 retronecine 酯多，海绿碱二酯化物产生的吡咯比 retronecine 二酯化物少，因为前者更容易受到水解攻击。

Levels of pyrrolic metabolites were measured in the livers of rats given some pyrrolizidine alkaloids and semisynthetic derivatives. ... Heliotridine-based alkaloids gave more pyrrole than similar retronecine esters, heliotridine ditiglate gave less pyrrole than retronecine ditiglate because the former was more open to hydrolytic attack.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 副作用

职业性肝毒素 - 第二性肝毒素：在职业环境中的毒性效应潜力是基于人类摄入或动物实验的中毒病例。

Occupational hepatotoxin - Secondary hepatotoxins: the potential for toxic effect in the occupational setting is based on cases of poisoning by human ingestion or animal experimentation.

来源:Haz-Map, Information on Hazardous Chemicals and Occupational Diseases

毒理性

• 解毒与急救

基本治疗：建立专利气道。如有必要，进行吸痰。观察呼吸不足的迹象，并在需要时辅助通气。通过非循环呼吸面罩以10至15升/分钟的速度给予氧气。监测肺水肿，并在必要时进行治疗……。监测休克，并在必要时进行治疗……。预期癫痫发作，并在必要时进行治疗……。对于眼睛污染，立即用水冲洗眼睛。在转运过程中，用生理盐水连续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能吞咽、有强烈的干呕反射且不流口水，则用水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释……。在去污后，用干燥的无菌敷料覆盖皮肤烧伤……。/毒药A和B/

Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

高级治疗：对于无意识、严重肺水肿或呼吸停止的患者，考虑进行口咽或鼻咽气管插管以控制气道。使用气囊面罩装置的正压通气技术可能有益。监测心率和必要时治疗心律失常。 ... 开始静脉输液，使用D5W/SRP：“保持开放”，最低流量/。如果出现低血容量的迹象，使用乳酸钠林格氏液。注意液体过载的迹象。考虑使用药物治疗肺水肿。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象。用地西泮（安定）治疗癫痫。使用丙美卡因氢氯化物协助眼部冲洗。/毒药A和B/

Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

表现取决于活跃的有毒物质。在大多数情况下，大量摄入后60到90分钟内会出现呕吐、腹痛和腹泻。某些毒素可能会导致严重的胃肠炎，进而导致大量的液体和电解质流失。...保持气道畅通，必要时协助呼吸。给予补充氧气。如果出现昏迷、癫痫、心律失常和低血压，则进行治疗。用静脉晶体液替换由胃肠炎引起的液体流失。...如果有的话，给予活性炭。如果及时给予活性炭，则不需要进行胃排空。 /植物和草药药物：第1组/

Presentation depends on the active toxic agent. In most cases, vomiting, abdominal pain, and diarrhea occur within 60 to 90 minutes of significant ingestion. With some toxins, severe gastroenteritis may result in massive fluid and electrolyte loss. ... Maintain open airway and assist ventilation if necessary. Administer supplemental oxygen. Treat coma, seizures, arrhythmias, and hypotension if they occur. Replace fluid loss caused by gastroenteritis with intravenous crystalloid solutions. ... Administer activated charcoal if available ... Gastric emptying is not necessary if activated charcoal is given promptly. /Plants and Herbal Medicines: Group 1/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

人类暴露研究/迄今为止报告的最大爆发发生在阿富汗西北部赫拉特省的古兰区，靠近苏联边境。...据估计，这次爆发影响了大约35,000人的98个村庄。对受影响村庄的7,200名居民进行检查，发现22.6%的人有疾病的证据，其中15%的情况更为严重。因此，估计大约有8,000人患有这种疾病，包括5,000人受到严重影响。所有年龄组都有受到影响，但46%的受试者年龄在14岁以下。然而，在2岁以下的儿童中没有发现疾病的迹象。关于从14个肝脏活检和8个尸检中获得的病理材料的详细报告已经完成...尽管没有指出症状出现和活检/尸检之间的时间间隔。病理发现具有特征性，范围从具有特征性静脉闭塞的急性疾病到非门脉肝硬化，这在上述22例中有5例观察到。这次爆发归因于小麦大规模污染，小麦是主要粮食作物，经过两年的干旱，与生长在小麦作物中的大量Heliotropium popovii H. Riedl亚种gillianum H. Riedl的种子混合。这些种子含有吡咯烷生物碱，两个实验室报告的浓度分别为7.2和13.2-14.9克/千克，主要被识别为heliotrine的N-氧化物（74%）...，还有一两种与lasiocarpine性质相似的化合物。来自几个村庄的小麦样本平均含有40粒种子/千克，即重量的0.03%。据估计，成年人每天至少消耗700克面粉，含有大约2毫克生物碱（基于种子分析的平均值）。/吡咯烷生物碱/

/HUMAN EXPOSURE STUDIES/ The largest outbreak reported to date occurred in the Gulran district of Herat Province in northwest Afghanistan, close to the border of the USSR. ...The outbreak, was estimated to have affected a population of approximately 35,000 in 98 villages. Examination of 7,200 inhabitants of the affected villages showed evidence of disease in 22.6%, which was more serious in 15%. Thus, it was estimated that approximately 8,000 subjects suffered from the disease including 5,000 who were seriously affected. All age groups were affected, but 46% of subjects were below 14 years of age. However, no sign of disease was found in children below 2 years of age. A detailed report concerning the pathological material obtained from 14 liver biopsies and 8 autopsies was made... /although/ the time interval between the onset of symptoms and the biopsy/autopsy was not indicated. Pathological findings were characteristic, ranging from acute disease with characteristic veno-occlusion to non-portal cirrhosis, which was observed in 5 of the above 22 cases. The outbreak was ascribed to massive contamination of wheat, the staple food crop, following 2 years of drought, with the seeds of Heliotropium popovii H. Riedl subsp. gillianum H. Riedl, which had been growing profusely among the wheat crop. The seeds contained pyrrolizidine alkaloids at concentrations reported by 2 laboratories to be 7.2 and 13.2-14.9 g/kg, identified mainly as the N-oxide of heliotrine (74%)..., and one or two other compounds similar in character to lasiocarpine. Samples of wheat from several villages contained an average of 40 seeds/kg, i.e., 0.03% by weight. It was estimated that an adult consumed at least 700 g flour/day, containing approximately 2 mg alkaloid (based on a mean of the seed analyses). /Pyrrolizidine alkaloids/

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 海关编码：
  2933990090

反应信息

• 作为反应物：
  描述：

  天芥菜定 在 4-二甲氨基吡啶 、 sodium hydride 作用下， 以 乙腈 为溶剂， 反应 48.0h， 生成 7-O-(Phenoxythiocarbonyl)-9-O-(tert-butyldimethylsilyl)heliotridine
  参考文献：
  名称：

  Free-radical reactions of retronecine and heliotridine derivatives. The synthesis of (-)-supinidine

  摘要：

  DOI：

  10.1021/jo00297a081
• 作为产物：
  描述：

  1-aza-4-(1,3-dithian-2-ylidene)-6(S)-(acetyloxy)bicyclo<3.3.0>octan-8-one 在 甲醇 、 lithium aluminium tetrahydride 、 potassium carbonate 、 calcium carbonate 、 mercury dichloride 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 甲醇 、 水 、 乙腈 为溶剂， 反应 27.0h， 生成 天芥菜定
  参考文献：
  名称：

  Synthesis of optically active pyrrolizidinediols: (+)-heliotridine

  摘要：

  DOI：

  10.1021/ja00349a051

文献信息

• α-Acylamino radical cyclizations using allenes and vinylsilanes as addends: applications to the synthesis of (+)-heliotridine and (-)-dihydroxyheliotridine
  作者：Jeffrey M. Dener、David J. Hart

  DOI：10.1016/s0040-4020(01)86072-5

  日期：1988.1

  Total syntheses of the pyrrolizidine bases (+)-heliotridine (4) and (-)-dihydroxyheliotridane (5) from (S)-3-acetoxysuccinimide are described. The syntheses of 4 and 5 revolve around free radical cyclizations involving the use of allenes and vinylsilanes, respectively, as addends.

  heliotridine（ -的双吡咯烷碱基（+）的全合成4）和（ - ） - dihydroxyheliotridane（5从（）小号）-3-乙酰氧基琥珀酰亚胺进行说明。4和5的合成围绕自由基环化反应，涉及分别使用丙二烯和乙烯基硅烷作为加成物。
• Free radical cyclizations in alkaloid synthesis: (+)-heliotridine and (+)-hastanecine
  作者：Joong-Kwon Choi、David J. Hart

  DOI：10.1016/s0040-4020(01)97176-5

  日期：1985.1

  hydride and AIBN affords mixtures of reduction and cyclization products. Cyclization products partition between indolizidinones and pyrrolizidinones depending on the terminal alkyne substituent. When the terminal substituent is a trimethylsilyl group, synthetically useful yields of pyrrolizidinones are obtained. Applications of this chemistry to the synthesis of (+)-heliotridine (2) and (+)-hastanecine (3)

  用氢化三丁基锡和AIBN处理苯硫内酰胺5a-f可得到还原和环化产物的混合物。取决于末端炔烃取代基，环化产物在吲哚啶酮和吡咯烷酮之间分配。当末端取代基是三甲基甲硅烷基时，可获得吡咯烷二酮的合成有用的产率。描述了该化学方法通过关键中间体37和38在合成（+）-氯代吡啶（2）和（+）-芥子碱（3）中的应用。
• Semisynthetic pyrrolizidine alkaloid N-oxide antitumor agents. Esters of heliotridine
  作者：Leon H. Zalkow、Jan A. Glinski、Leslie T. Gelbaum、David Moore、Deborah Melder、Garth Powis

  DOI：10.1021/jm00403a008

  日期：1988.8

  lbutyric acid were prepared, converted into their N-oxides, and compared with the corresponding C-9 monoesters of retronecine in the in vivo P388 lymphocytic leukemia screen. Relative in vitro cytotoxicities of some of the free bases and their corresponding N-oxides were also measured against the A204 rhabdomyosarcoma cell line by using the soft agar colony forming assay. Stereochemistry at C-7 of

  制备了带有（S）-（+）和（R）-（-）-2-羟基-2-羟基丁酸的Heliotridine的C-9和C-7单酯以及C-7，C-9二酯，将其转化为在体内P388淋巴细胞白血病筛查中，将其N氧化物与相应的逆转录酶C-9单酯进行比较。通过使用软琼脂菌落形成试验，还测量了一些游离碱及其相应的N-氧化物对A204横纹肌肉瘤细胞系的相对体外细胞毒性。烟碱的C-7和烟酸的C-2'的立体化学似乎对该系统的抗肿瘤活性具有显着影响。在Heliotridine系列中，烟酸的构型对碳二咪唑酯化反应中的位点选择性（C-7与C-9）有显着影响。提供了该位点选择性的解释。
• Pyrrolizidine alkaloids of the endemic Mexican genus Pittocaulon and assignment of stereoisomeric 1,2-saturated necine bases
  作者：Juan Camilo Marín Loaiza、Ludger Ernst、Till Beuerle、Claudine Theuring、Carlos L. Céspedes、Thomas Hartmann

  DOI：10.1016/j.phytochem.2007.07.004

  日期：2008.1

  allows the separation and identification of the four stereoisomers as their diacetyl or trimethylsilyl derivatives. All otonecine esters that generally do not form N-oxides and the 1,2-saturated PAs were exclusively found as free bases, while the 1,2-unsaturated 7-angeloylheliotridine occurring in P. velatum was found only as its N-oxide. In a comparative study the 1H and 13C NMR spectra of the four stereoisomeric

  墨西哥特有属 Pittacaulon（亚部落 Tussilagininae，部落 Senecioneae，菊科）属于分布在墨西哥和北美洲的单系属群。五种 Pittacaulon 物种代表具有扫帚状多汁枝条的灌木。所有物种都被发现含有吡咯里西啶生物碱 (PAs)。除了一个例外（即，Pittacaulon velatum 的茎不含 PA），在所有植物器官中都发现了 PA，在花头中含量最高（高达干重的 0.3%）。发现了三种结构类型的PA：（1）大环奥托辛酯，例如senkirkine和acetylpetasitenine；(2) 仅在根中发现的大环反花碱酯，例如千叶花碱，和 (3) 1,2-饱和花花碱与当归酸的单酯。对于不同立体异构体 1 的明确分配，2-饱和的necine 碱基建立了GC-MS 方法，该方法允许将四种立体异构体作为它们的二乙酰或三甲基甲硅烷基衍生物进行分离和鉴定。通常不形成 N-氧化物的所有
• Expedient Pyrrolizidine Synthesis by Propargylsilane Addition to<i>N</i>-Acyliminium Ions followed by Gold-Catalyzed α-Allenyl Amide Cyclization
  作者：Arjen C. Breman、Jan Dijkink、Jan H. van Maarseveen、Sape S. Kinderman、Henk Hiemstra

  DOI：10.1021/jo901393y

  日期：2009.8.21

  A reaction sequence, involving the addition of (substituted) propargylsilanes to lactam-derived N-acyliminium ions followed by gold-catalyzed cyclization of the resulting α-allenyl amide, is applied in expedient syntheses of pyrrolizidine alkaloids heliotridine and ent-retronecine in five steps from (S)-malic acid.

  在五个步骤中，将反应顺序（包括将（取代的）炔丙基硅烷添加到内酰胺衍生的N-酰基亚胺离子中，然后用金催化的环化所得的α-烯丙基酰胺）进行吡咯烷核生物碱类四氢吡啶和对-维甲酸的合成来自（S）-苹果酸。