瑞氏千里光碱 | 23246-96-0

• 分子结构分类: 有机化合物 - 生物碱及其衍生物
• 中文名称: 瑞氏千里光碱
• 英文名称: riddelliine
• 英文别名: riddelline；Riddeline；(1R,4Z,7S,17R)-4-ethylidene-7-hydroxy-7-(hydroxymethyl)-6-methylidene-2,9-dioxa-14-azatricyclo[9.5.1.014,17]heptadec-11-ene-3,8-dione
• CAS: 23246-96-0
• 化学式: C₁₈H₂₃NO₆
• 分子量: 349.384
• InChiKey: SVCNNZDUGWLODJ-RAYFHMIRSA-N

物化性质

• 熔点：
  197.5°C (rough estimate)
• 沸点：
  483.56°C (rough estimate)
• 密度：
  1.2966 (rough estimate)
• 物理描述：
  Riddelline is a colorless to off-white crystalline solid. Starts turning brown at approximately 329°F; is blackish-brown at melting point. (NTP, 1992)
• 溶解度：
  less than 1 mg/mL at 77° F (NTP, 1992)
• 稳定性/保质期：

  Stability: stable at room temperature in closed containers: best stored under nitrogen -15 °C.

• 分解：
  When heated to decomposition it emits toxic fumes of /nitrogen oxide/.

计算性质

• 辛醇/水分配系数(LogP)：
  0.2
• 重原子数：
  25
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  96.3
• 氢给体数：
  2
• 氢受体数：
  7

ADMET

代谢

在经过苯巴比妥预处理的Fischer 344大鼠肝微粒体中，经过30分钟有氧培养后，利德尔碱的主要代谢物是利德尔碱N-氧化物和脱氢雷特罗内氨酸。

In liver microsomes of Fischer 344 rats pretreated with phenobarbital, the major metabolites of riddelliine obtained after aerobic incubation for 30 min were riddelliine N-oxide and dehydroretronecine ... .

来源:Hazardous Substances Data Bank (HSDB)

代谢

在动物中，吡咯烷生物碱的主要代谢途径是：(a) 酯基的水解；(b) N-氧化；和(c) 吡咯烷环的脱氢生成吡咯衍生物。途径(a)和(b)被认为是解毒机制。途径(c)导致有毒代谢物。途径(a)发生在肝脏和血液中；途径(b)和(c)是通过微粒体混合功能氧化酶系统在肝脏中产生的。/吡咯烷生物碱/

In animals, the major metabolic routes of pyrrolizidine alkaloids are: (a) hydrolysis of the ester groups; (b) N-oxidation; and (c) dehydrogenation of the pyrrolizidine nucleus to pyrrolic derivatives. Routes (a) and (b) are believed to be detoxification mechanisms. Route (c) leads to toxic metabolites. Route (a) occurs in liver and blood; routes (b) and (c) are brought about in the liver by the microsomal mixed function oxidase system. /pyrrolizidine alkaloids/

来源:Hazardous Substances Data Bank (HSDB)

代谢

... 瑞德利碱及其两种代谢物，N-氧化物和瑞托尼碱，在大鼠和小鼠口服灌胃剂量后的血清中的毒物代谢动力学通过一种经过验证的液相色谱-电喷雾质谱法进行了测定。结果表明，瑞德利碱及其极性更大的代谢物在排泄之前被广泛代谢。因此，可以得出结论，除了毒物代谢动力学之外，还有其他因素负责大鼠和小鼠观察到的物种/性别特异性的总体毒性或肝脏肿瘤诱导。

... The toxicokinetics of riddelliine and two metabolites, the N-oxide and retronecine, were determined in serum following an oral gavage dose in male and female rats and mice using a validated liquid chromatography-electrospray mass spectrometric method. The results are consistent with extensive metabolism of riddelliine and its more polar metabolites prior to excretion. It is concluded that factors other than toxicokinetics are responsible for the observed species/sex specificity of gross toxicity or liver tumor induction in rats and mice.

来源:Hazardous Substances Data Bank (HSDB)

代谢

为了确定在实验动物中获得的成果对人类的相关性，研究了利用人肝微粒体进行的利德尔因的代谢。与大鼠肝微粒体一样，DHP（二氢吡咯氮杂）和利德尔因N-氧化物是人肝微粒体培养中的主要代谢物。(+/-)-6,7-二氢-7-羟基-1-羟甲基-5H-吡咯氮杂（DHP）和利德尔因N-氧化物的水平分别为0.20-0.62和0.03-0.15 nmol/min/mg蛋白质，这与从大鼠肝微粒体代谢中获得的水平相当。当在存在小牛胸腺DNA的情况下进行代谢时，形成了相同的一组八个DHP衍生的DNA加合物。无论是代谢模式还是DNA加合物谱，都与从大鼠肝微粒体中获得的结果非常相似。当在存在P450 3A4酶抑制剂三乙酰瑞德霉素的情况下进行代谢时，DHP和利德尔因N-氧化物的形成分别减少了84%和92%。对于DHP的形成，从雌性大鼠和雌性人体中确定的Km值分别为0.37 +/- 0.05和0.66 +/- 0.08 mM；从雌性大鼠和人体肝微粒体代谢中获得的Vmax值分别为0.48 +/- 0.03和1.70 +/- 0.09 nmol/min/mg蛋白质。

... To determine the relevance to humans of the results obtained in experimental animals, the metabolism of riddelliine was conducted using human liver microsomes. As with rat liver microsomes, DHP and riddelliine N-oxide were major metabolites in incubations conducted with human liver microsomes. The levels of (+/-)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP) and riddelliine N-oxide were 0.20-0.62 and 0.03-0.15 nmol/min/mg protein, respectively, which are comparable to those obtained from rat liver microsomal metabolism. When metabolism was conducted in the presence of calf thymus DNA, the same set of eight DHP-derived DNA adducts was formed. Both the metabolism pattern and DNA adduct profile were very similar to those obtained from rat liver microsomes. When metabolism was conducted in the presence of the P450 3A4 enzyme inhibitor triacetyleandomycin, the formation of DHP and riddelliine N-oxide was reduced 84 and 92%, respectively. For DHP formation, the Km values were determined to be 0.37 +/- 0.05 and 0.66 +/- 0.08 mM from female rats and female humans; the Vmax values from female rat and human liver microsomal metabolism were 0.48 +/- 0.03 and 1.70 +/- 0.09 nmol/min/mg protein, respectively.

来源:Hazardous Substances Data Bank (HSDB)

代谢

... F344雌性大鼠肝脏微粒体对瑞德雷因的代谢产生了瑞德雷因N-氧化物和脱氢瑞特诺尼西因（DHR）作为主要代谢物。当使用苯巴比妥处理的大鼠肝脏微粒体时，代谢作用增强。在存在小牛胸腺DNA的情况下进行代谢，产生了8种与DHR与小牛胸腺DNA反应得到的DNA加合物相同的DNA加合物。

... Metabolism of riddelliine by liver microsomes of F344 female rats generated riddelliine N-oxide and dehydroretronecine (DHR) as major metabolites. Metabolism was enhanced when liver microsomes from phenobarbital-treated rats were used. Metabolism in the presence of calf thymus DNA resulted in eight DNA adducts that were identical to those obtained from the reaction of DHR with calf thymus DNA.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 致癌性证据

评估：目前没有关于千里光碱对人类致癌性的数据。在实验动物中有足够的证据表明千里光碱具有致癌性。总体评估：千里光碱可能对人类具有致癌性（2B组）。

Evaluation: There are no data on the carcinogenicity of riddelliine to humans. There is sufficient evidence in experimental animals for the carcinogenicity of riddelliine. Overall evaluation: Riddelliine is possibly carcinogenic to humans (Group 2B).

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 致癌物分类

国际癌症研究机构致癌物：千里光碱

IARC Carcinogenic Agent:Riddelliine

来源:International Agency for Research on Cancer (IARC)

毒理性

• 致癌物分类

国际癌症研究机构（IARC）致癌物分类：2B组：可能对人类致癌

IARC Carcinogenic Classes:Group 2B: Possibly carcinogenic to humans

来源:International Agency for Research on Cancer (IARC)

毒理性

• 致癌物分类

国际癌症研究机构专著：第10卷：(1976年)一些自然存在的物质 增补第7卷：致癌性的整体评估：对国际癌症研究机构专著第1至42卷的更新，1987年；440页；ISBN 92-832-1411-0（已绝版） 第82卷：(2002年)一些传统草药药物，一些霉菌毒素，萘和苯乙烯

IARC Monographs:Volume 10: (1976) Some Naturally Occurring Substances Volume Sup 7: Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs Volumes 1 to 42, 1987; 440 pages; ISBN 92-832-1411-0 (out of print) Volume 82: (2002) Some Traditional Herbal Medicines, Some Mycotoxins, Naphthalene and Styrene

来源:International Agency for Research on Cancer (IARC)

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案例。

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

吸收、分配和排泄

几个喂养实验表明，riddelliine（瑞德利宁）及其N-氧化物（氮氧化物）在家养农场动物的胃肠中被吸收。用riddelliine N-氧化物（40 mg/kg/天）或riddelliine N-氧化物（40.5 mg/kg/天）和riddelliine（4.5 mg/kg/天）的混合物治疗20天的牛犊，其发病率达到100%，这意味着在每种情况下都有吸收。用不同剂量的riddelliine（3、10或15 mg/kg体重，以明胶胶囊形式）喂养40天的猪的组织样本也显示了吸收，这是通过液相色谱和串联质谱法分析血液和肝脏样本中吡咯代谢物确定的，这些样本是在治疗结束一天后收集的。

Several feeding experiments have indicated that riddelliine and its N-oxide are absorbed in the gastrointestinal tract of domestic farm animals. Calves treated for 20 days with either riddelliine N-oxide (40 mg/kg/day) or a mixture of riddelliine N-oxide (40.5 mg/kg/day) and riddelliine (4.5 mg/kg/day) showed 100% morbidity, implying absorption in each case. Tissue samples from pigs fed various amounts (3, 10 or 15 mg/kg body weight in gelatin capsules) of riddelliine for 40 days also showed absorption, as determined by liquid chromatography and tandem mass spectrometric analysis of pyrrolic metabolites in blood and liver samples collected one day after the end of treatment.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在动物研究中，最高浓度被发现于肝脏、肺、肾脏和脾脏。/吡咯烷生物碱/

In animal studies highest concentrations were found in the liver, lungs, kidneys and spleen. /pyrrolizidine alkaloids/

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1(b)
• 包装等级：
  III
• 危险类别：
  6.1(b)
• 危险品运输编号：
  UN 1544

制备方法与用途

生物活性方面，Riddelline 是一种吡咯利西啶生物碱，具有基因毒性。研究表明，它能诱导大鼠肝脏中非计划DNA的合成，并促使细胞进入S期。

反应信息

• 作为反应物：
  描述：

  瑞氏千里光碱 在 吡啶 、 N,N'-二环己基碳二亚胺 作用下， 以 氯仿 为溶剂， 反应 33.0h， 生成 Succinic acid 2,5-dioxo-pyrrolidin-1-yl ester (4aR,10S,13bR)-7-eth-(Z)-ylidene-10-hydroxy-9-methylene-6,11-dioxo-2,3,4,4a,6,7,8,9,10,11,13,13b-dodecahydro-5,12-dioxa-2a-aza-cyclododeca[cd]pentalen-10-ylmethyl ester
  参考文献：
  名称：

  肝毒性生物碱riddelliine和riddelliine N-oxide的酶联免疫吸附测定方法的开发。

  摘要：

  含吡咯烷核生物碱的植物广泛分布于世界各地，在千里光属中尤为常见。生物碱的结构类型和浓度随植物种类而变化。另外，在一种植物中，浓度随环境和位置而变化。许多吡咯嗪核生物碱有毒，会导致牲畜和人类中毒。需要快速，灵敏和特定的诊断技术来识别中毒的动物，并确定牲畜可能中毒的特定植物和条件。在这项研究中，使用多克隆抗体开发了两种竞争性抑制酶联免疫吸附测定法，分别用于riddelliine，riddelliine N-oxide和其他密切相关的吡咯烷核生物碱。一种测定法是对吡咯烷核生物碱的游离碱形式具有特异性的测定法。另一种测定显示了与生物碱的游离碱和N-氧化物形式的交叉反应性。最低检出限的测定的I（50）为803.9 pg，对riddelliine的检出限为47.5 pg。牛血中riddelliine的峰值和恢复研究范围为45％到74％。该测定法显示了吡咯烷啶生物碱的N-氧化物和游离碱形式之间的交叉反应

  DOI：

  10.1021/jf010042m

文献信息

• Full Structure Assignments of Pyrrolizidine Alkaloid DNA Adducts and Mechanism of Tumor Initiation
  作者：Yuewei Zhao、Qingsu Xia、Gonçalo Gamboa da Costa、Hongtao Yu、Lining Cai、Peter P. Fu

  DOI：10.1021/tx300292h

  日期：2012.9.17

  for these DNA adducts, enabling their full structural elucidation by mass spectrometry and NMR spectroscopy. We determined that DHP-dA-3 and DHP-dA-4 are a pair of epimers of 7-hydroxy-9-(deoxyadenosin-N6-yl) dehydrosupinidine, while DHP-dG-4 is 7-hydroxy-9-(deoxyguanosin-N2-yl)dehydrosupinidine, an epimer of DHP-dG-3. With the structures of these DNA adducts unequivocally elucidated, we conclude that

  含吡咯烷酮生物碱的植物在世界范围内广泛存在，可能是影响牲畜，野生动植物和人类的最常见的有毒植物。吡咯烷核生物碱是在植物中鉴定出的首批化学致癌物。以前，我们确定吡咯并立核生物碱在体内和体外的代谢产生了一组常见的DNA加合物，这些加合物负责诱导肿瘤。使用LC-ESI / MS / MS分析，我们先前确定在使用riddelliine剂量的大鼠中形成了四个DNA加合物（DHP-dG-3，DHP-dG-4，DHP-dA-3和DHP-dA-4）。 ，一种致癌的吡咯烷核生物碱。由于缺乏足够的真实标准品，DHP-dA-3和DHP-dA-4的结构尚未阐明，DHP-dG-4的结构分配值得进一步验证。在这项研究中，我们为这些DNA加合物开发了一种改进的合成方法，从而可以通过质谱和NMR光谱对它们的完整结构进行阐明。我们确定DHP-dA-3和DHP-dA-4是7-羟基-9-（脱氧腺苷-D 6 -D 6是DHP-d
• 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-
• Human Liver Microsomal Metabolism and DNA Adduct Formation of the Tumorigenic Pyrrolizidine Alkaloid, Riddelliine
  作者：Qingsu Xia、Ming W. Chou、Fred. F. Kadlubar、Po-Cheun Chan、Peter P. Fu

  DOI：10.1021/tx025605i

  日期：2003.1.1

  obtained from rat liver microsomal metabolism. When metabolism was conducted in the presence of calf thymus DNA, the same set of eight DHP-derived DNA adducts was formed. Both the metabolism pattern and DNA adduct profile were very similar to those obtained from rat liver microsomes. When metabolism was conducted in the presence of the P450 3A4 enzyme inhibitor triacetyleandomycin, the formation of DHP and

  利得利宁是一种广泛存在的天然遗传毒性吡咯烷啶生物碱，在一项为期2年的NTP致癌生物测定法中，可在大鼠和小鼠中诱发肝脏肿瘤。我们已经确定，riddelliine通过遗传毒性机制诱导大鼠肝肿瘤，该机制涉及（+/-）-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine（DHP）的形成，该反应与DNA发生反应。形成一组八个DNA加合物。为了确定在实验动物中获得的结果与人的相关性，使用人肝微粒体进行了riddelliine的代谢。与大鼠肝微粒体一样，DHP和riddelliine N-氧化物是与人肝微粒体温育的主要代谢产物。DHP和riddelliine N-氧化物的水平分别为0.20-0.62和0.03-0.15 nmol / min / mg蛋白，与从大鼠肝脏微粒体代谢中获得的代谢物相当。当在小牛胸腺DNA的存在下进行新陈代谢时，会形成同一组
• Method for predicting a subject's response to valproic acid therapy
  申请人：THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK

  公开号：US11041207B2

  公开（公告）日：2021-06-22

  The present invention provides, inter alia, methods for treating or ameliorating the effects of a disorder, such as schizophrenia or bipolar disorder, by increasing or decreasing proline levels. Further provided are methods of predicting and monitoring the clinical response in a patient, and diagnostic systems for identifying a patient likely to benefit from proline modulation.

  本发明特别提供了通过增加或减少脯氨酸水平来治疗或改善精神分裂症或双相情感障碍等疾病的方法。本发明还提供了预测和监测患者临床反应的方法，以及用于识别可能从脯氨酸调节中获益的患者的诊断系统。
• METHOD FOR PREDICTING A SUBJECTS RESPONSE TO SLC MODULATOR THERAPY
  申请人：THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK

  公开号：US20210254158A1

  公开（公告）日：2021-08-19

  The present invention provides, inter alia, methods for treating or ameliorating the effects of a disorder, such as schizophrenia or bipolar disorder, by increasing or decreasing proline levels. Further provided are methods of predicting and monitoring the clinical response in a patient, and diagnostic systems for identifying a patient likely to benefit from proline modulation.